Brain Facts Book 2018 High Res PDF

A PRIMER ON THE BRAIN AND NERVOUS SYSTEM
A Companion Publication to BrainFacts.org

Know Your Brain,
Know Yourself
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— the eight ideas that people need to know about
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purpose is to help you understand your brain —
Eighth Edition
because when you know your brain, you
Brain Facts is printed on Burgo Chorus Art know yourself.
Silk, made with 30% post-consumer waste, As you peruse this new edition of Brain Facts,
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ing Core Concepts, we have expanded the book
to include chapters on the teenage brain as well
as on thinking and decision-making. There are
more than 30 images from neuroscience that will
enhance your understanding of everything from
neurogenesis to neural networks. In addition,
the glossary has been rewritten and reviewed to
include nearly 80 new key terms.
A PRIMER ON THE BRAIN AND NERVOUS SYSTEM
A companion to BrainFacts.org
A PUBLIC INFORMATION INITIATIVE OF:

Contributors
T
he Society for Neuroscience (SfN) would like to thank the dedicated team of SfN
members — neuroscientists that volunteered their time and expertise — that
guided and reviewed the eighth revision of Brain Facts. It is commitments such
as these that build communities invested in science education, public outreach, and the
advancement of the ever-evolving field of neuroscience.
SfN also recognizes the significant contributions of Charles Yokoyama, PhD,

Suzana Herculano-Houzel, PhD, Public Education and Communication Committee Chair
Frances Jensen, MD, and BrainFacts.org Editor-in-Chief, John Morrison, PhD.
Scientific Review: Angela Jane Roskams, PhD; Charles Jennings, PhD; Charles Yokoyama,
PhD; Ed Bilsky, PhD; Emanuel DiCicco-Bloom, PhD; Frances Jensen, MD; James
Giordano, PhD; John Morrison, PhD; Katalin Gothard, PhD; Kelley Remole, PhD;
Lise Eliot, PhD; Martha Farah, PhD; Maya Sapiurka, PhD; Rebecca Shansky, PhD;
Richard Wingate, PhD; Roberta Diaz Brinton, PhD; Robert Greene, PhD; Roberto
Caminiti, MD; Rochelle Schwartz-Bloom, PhD; Sarah Dunlop, PhD; Stuart Firestein,
PhD; Tracy Bale, PhD
Senior Director, Communications & Marketing: Kara Flynn
Executive Editor: Lisa Chiu
Production Editors: Alexis Wnuk, Emma Lindberg, Juliet M. Beverly, and

Michael Richardson
Managing Editor: Jacquelyn Beals
Copy Editors: Kristina Reznikov and Randi Henderson
Writers: Alexis Wnuk, Alison Davis, Clinton Parks, Deborah Halber, Diane Kelly,
Gail Zyla, Karen Hopkin, Karen Weintraub, Juliet M. Beverly, Knvul Safia Sheikh,
Lindzi Wessel, Lisa Chiu, Marissa Fessenden, Melissa Galinato, Michael Richardson,
Sandra Blumenrath, Susan Rojahn
Illustrators: Lydia V. Kibiuk, Baltimore, MD; Devon Stuart, Hershey, PA; Matt Wimsatt,
Brooklyn, NY; Richard Lewis Media Group, Watertown MA
Consultant: Hilary Gerstein, PhD
Layout and Design: Dever Designs
2 Brain Facts | society for neuroscience

Contents
INTRODUCTION 4
CHAPTER 1 Brain Basics 10
CHAPTER 2 Senses & Perception 18
CHAPTER 3 Movement 26
CHAPTER 4 Learning, Memory & Emotions 32
CHAPTER 5 Thinking, Planning & Language 38
CHAPTER 6 The Developing Brain 44
CHAPTER 7 Infant, Child & Adolescent Brain 49
CHAPTER 8 Adult & Aging Brain 53
CHAPTER 9 Brain States 59
CHAPTER 10 The Body in Balance 66
CHAPTER 11 Childhood Disorders 71
CHAPTER 12 Psychiatric Disorders 76
CHAPTER 13 Addiction 81
CHAPTER 14 Injury & Illness 88
CHAPTER 15 Neurodegenerative Diseases 96
CHAPTER 16 Kinds of Research 105
CHAPTER 17 Solving Human Problems 112
CHAPTER 18 Neuroscience in Society 118
G L O S S A R Y 122
NEUROSCIENCE RESOURCES 128
I N D E X 129
society for neuroscience | Brain Facts 3

Introduction
N
euroscience is rapidly advancing what we know about the brain, the nervous
system, and ourselves. It’s often difficult to keep up with every discovery. Just as
we were producing this book, The Brain Prize for 2017 was awarded to neurosci-
entists whose research explains the brain’s learning and reward system. That discovery helps
us to understand the behaviors that trigger compulsive gambling and drug and alcohol ad-
diction. Then, the 2017 Nobel Prize for Medicine or Physiology honored researchers who
revealed the inner workings of circadian rhythms, our body’s internal clock, and The Brain
Prize for 2018 recognized discoveries about the underlying mechanisms of neurodegenera-
tive diseases such as Alzheimer’s and Parkinson’s disease.
Discovery doesn’t happen overnight, but the field has generated significant eureka
moments since our last edition. Here we can take a moment to slow down and explore the
fundamentals behind the research and discoveries that have built neuroscience. This eighth
edition of Brain Facts contains our most current understanding of what we know today
about the brain while addressing emerging topics in the field.
Underpinning every new discovery are the concepts and principles that neuroscientists
have established in more than a century of studying the brain. Members of the Society for
Neuroscience articulated those concepts more than a decade ago as Core Concepts — the
eight ideas that people need to know about their brain and nervous system. Here, Core
Concepts provide touchstones for deepening your understanding of the material presented.
For example, information about circadian rhythms fits into the context of the concept that
the brain uses specific circuits to process information. The role of the learning and reward
systems in behaviors such as compulsive gambling and addiction illustrates the concept that
the brain uses inference, emotion, memory, and imagination to make predictions.
Core Concepts icons throughout the text offer you the opportunity to place informa-
tion in the book into the wider context of neuroscience as a whole. They serve as a foun-
dation upon which you can build more detailed knowledge. If you need a reference point,
don’t forget to use the extended cover flap to remind you of the Core Concepts along the
way, or as a bookmark during your reading.

NEUROSCIENCE CORE CONCEPTS
Your Complex Brain
A human brain contains roughly similarities with the human nervous system.
86 billion nerve cells, or neurons. Contrary The nervous system keeps our bodies in
to popular misconception, we use all of the sync by communicating with all other
neurons in our brains, not just some small parts of our bodies, like the cardiovascular
fraction of them. system, the gastrointestinal system, the
Each of those neurons exchanges immune system, etc. With so many inter-
electrical signals with thousands of other connected parts, however, there are endless
neurons to create the countless circuits that, ways for things to go wrong. From Alzhei-
along with the nerves throughout our bod- mer’s disease to depression, an estimated
ies, form our nervous system. In the course one in four people worldwide will face a
of millions of years, our nervous systems neurological or psychiatric condition, caus-
have evolved from much simpler begin- ing enormous financial and social burdens.
nings. Roundworms, fruit flies, zebrafish, The promise of solving these problems lies
salamanders, mice, and monkeys all possess in unraveling the mysteries of the brain
nervous systems that share fundamental and nervous system.
How Neurons Communicate
Your brain can serve as your body’s message, which crosses the gap, called a
command center because neurons commu- synapse. The release of chemical messengers
nicate with each other. They relay messages can trigger a second action potential in the
throughout your body and power all of neuron on the other side of the synapse,
your thoughts and actions. Neurons talk conveying the message onward or, when
to each other using both electrical and the action potential triggers the release of a
chemical signals. chemical messenger that blunts the trans-
When you stub your toe, sensory mission of a signal, quelling the message.
neurons create electrical signals, called This happens over and over, and with
action potentials, which travel rapidly repeated activity, the synapse grows stron-
down a neuron. Those electrical signals, ger, so the next message is more likely to get
however, cannot cross the gap between through. That way, neurons learn to pass
two neurons. on important messages and ignore the rest.
In order to communicate, the action This is how our brains learn and adapt to an
potential is transformed into a chemical ever-changing world.

introduction continued
How Your Brain Processes Information
Your nervous system is filled with around you require complex circuits.
circuits made up of neurons that relay All of these circuits arise before you’re
messages around your brain and body. born, when genes direct neurons to as-
They’re responsible for everything you semble simple circuits in your developing
think, do, say, and feel. Sensory circuits brain. As your neurons and their connec-
carry signals from sense receptors to your tions change from new experiences and
brain. Motor circuits send commands to environments, those simple circuits become
your muscles. Simple circuits carry out much more complex. These changes hap-
your automatic reflexes. pen mostly in childhood but continue over
Higher-level activities like memory, your whole life — all a part of building a
decision-making, and perceiving the world better brain.
How Experience Shapes Your Brain
You’ve had most of the neurons in regain lost abilities — rerouting connections
your brain since birth. Most of those will and sometimes even growing new neu-
stick around for the rest of your life, yet rons, but only quite slowly if at all. At the
your brain is constantly changing — neu- same time, in a healthy brain neurons die
roscientists call this plasticity. Learn a new off, too. During development, the human
skill or language and your brain reacts by brain grows an excess of neurons. Early in
strengthening or weakening the connections life, the brain eliminates those extra cells,
between neurons — even creating new ones. keeping only those connections you need in
Each new experience shapes your brain to a process called synaptic pruning. Later on,
become uniquely yours. unused neurons can wither away. Physical
That capacity to change is vital. A brain and mental exercise preserves them, keeping
damaged by injury or disease may eventually your brain healthy.

Reasoning, Planning & Solving Problems
Your brain’s roughly 86 billion inter- associates the pictures it assembles with
connected neurons endow it with the ability feelings to form memories. Our brains store
to understand the world, plan actions, and those memories, learn from them, and use
solve problems. Doing so requires the brain that knowledge in the future. By combining
to incorporate all available information. By all of these tools with imagination, your
combining information from all of your brain can predict future events, calculate
body’s senses, the brain paints a picture of your next move, and devise plans for future
the world around you. Then, using infer- opportunities. Consciousness requires that
ence and instinct, the brain makes sense of all of these activities function normally. In
the picture it assembles. other words, your brain’s trillions of con-
The brain both makes and uses emo- nections work together to understand the
tions, which are value judgments that help world, to think about the future, and to
the brain respond effectively to events. It create … you.
The Power of Language
One thing that makes humans special the cortex form circuits that interpret the
is our talent for talking. Whether it’s a sounds and symbols of language.
professor’s technical discourse or a late night We use those circuits to generate words,
comic’s zingy one-liner, humans communi- turn them into sounds, and understand the
cate in ways that are far more complex than sounds we hear back. From birth, our brains
those of other animals because our brains are primed to learn language. Language en-
are amply wired for it. dows us with thoughts and creativity. With
Compared with other animals, the it, we can trade ideas and information, share
human brain possesses an enormous cere- our observations, and let others build on
bral cortex that is brimming with neural our discoveries. Over time, that has led to
circuits dedicated to language. Neurons in human culture and all of the inventions of
the temporal, parietal, and frontal lobes of modern society.

introduction continued
The Source of Curiosity
Did you know that your brain runs on of them work together to let you talk, learn,
only 25 watts of electricity — enough to pow- and imagine. We are learning why sugar
er an LED light bulb? Or that there are nearly is so hard to avoid, how exercise helps the
10,000 different types of neurons in your brain, and why the urge to scratch when
brain? The fact that we know these things — we have an itch is so irresistible.
or even care — is due to a special ability that Along the way, this exploration has led
arises in our complex brains: curiosity. to innumerable insights that have helped us
From a very early age, curiosity drives to solve human problems. We have treat-
us to understand our world, our communi- ments for pain and Parkinson’s disease, and
ties, our bodies, and even our own brains. more are on their way. Depression and
For the last two hundred years, the study Alzheimer’s disease are divulging their
of neuroscience has allowed us to do just secrets. Still, much remains to be learned
that. We’ve learned how individual neurons about the brain, and there are many more
work at a molecular level, and how billions discoveries to be made.
How Research Benefits Human Health
The United Nations estimates that other medical professionals to carefully test
neurological and psychiatric conditions the remedy in animals and, eventually, in
like Alzheimer’s disease, Parkinson’s disease, humans. If it proves safe and effective in those
and depression afflict one in four people tests, the medicine is approved for patients
worldwide. They cause more total disabil- nationwide. Researchers have been using that
ity than do heart attacks, cancers, or HIV/ process to fight the devastation of neurologi-
AIDS each year, inflicting profound suf- cal disorders and mental illness for decades.
fering and robbing patients of health and In the 1950s and ’60s, it led to the med-
independence. In doing so, they also leach ication L-dopa, which has helped millions of
an estimated $1.5 trillion from the U.S. patients to beat back symptoms of Parkin-
economy alone. Those numbers, and the son’s disease. In the 1990s, it yielded a class
human stories behind them, are among the of drugs called Selective Serotonin Reuptake
driving forces behind neuroscience. Inhibitors, like Prozac, to treat depression.
Neuroscientists study the biology of Today, neuroscience research is leading to
nerves and the brain, in both animals and promising advances for a host of conditions,
humans, in order to understand these from Alzheimer’s disease to epilepsy to schizo-
destructive conditions — and ultimately phrenia. In a field in which every advance has
find a treatment or cure. When a promising the chance to help ease suffering, research is
treatment emerges, neuroscientists work with more than a job: It’s a human imperative.

Coulthard, et al. Journal of Neuroscience, 2017.
To study the human brain, sometimes a petri dish is more useful than the real thing. This image shows a neural
rosette, a model of the developing human brain that scientists use to study how new cells are born.
In the center of the rosette are precursor cells, specialized cells that create new neurons and glia by dividing
themselves. The red ring is a visualization of the connections between these precursor cells. As they generate
new neurons and glia, the newborn cells radiate out from the center of the rosette to the outer edge of the brain
using the precursor cells as a scaffolding, marked in green. With this model, scientists can directly observe the
processes behind the developing human brain from the earliest stages.

CHAPTER
1
Brain Basics T
he brain is literally the “nerve
center” of your body — it
contains billions of neurons
that transmit information from the
body and the outside world, and
then programs our responses — con-
scious and unconscious movements,
thoughts, emotions, and memories.
What’s more, your brain can do all
these things simultaneously: You can
throw a ball while talking to a friend,
plan dinner while you’re shopping, or
daydream about a balloon ride as you
drive to work. Your brain can pull off
these feats of multitasking because it
is split into many distinct regions spe-
cialized for specific tasks and abilities.
Major Brain Landmarks

The largest part of the human
brain is the cerebrum. It is
divided into two large, separate
hemispheres, one on the left side, the
other on the right. The hemispheres
are connected by bundles of nerve
fibers that carry information from one
side of your brain to the other. The
largest of these bundles forms a bridge
between the cerebral hemispheres and
is called the corpus callosum.
The surface of the cerebrum is
a deeply folded layer of nerve tissue
called the cerebral cortex. Its deep
folds increase the area of the cerebral
cortex, creating space in this surface
layer for more neurons, which increase
the brain’s processing power. Just as
explorers use landmarks like rivers
and mountain ranges to describe and
map continents, neuroscientists use
the deepest divisions of the cerebrum
to identify regions of each hemisphere
as separate lobes — distinct regions
that have characteristic functions. This
“brain map” will serve as a useful trail
guide as you explore the brain in the
chapters ahead.
Brain Basics 1
The frontal lobes are at the front of

the brain, immediately above the eyes.
Parts of these lobes coordinate volun-
tary movements and speech, memory
and emotion, higher cognitive skills
like planning and problem-solving, and
many aspects of personality.
The parietal lobes are located at
the top of the brain, immediately be-
hind the frontal lobes. They integrate
sensory signals from the skin, process
taste, and process some types of
visual information.
The back of the brain houses the
occipital lobes. They process visual
information and are responsible for
recognizing colors and shapes and
Henry Vandyke Carter
integrating them into complex

visual understanding.
The temporal lobes lie on the
sides of the brain, at and below the
level of the eyes. They carry out Pictured are the brain’s four principal lobes. The frontal lobe, responsible for attention,
planning, and decision-making, is labeled blue. The temporal lobe, associated with language,
some visual processing and interpret memory, and emotion, is labeled in green. The parietal lobe, which integrates information from
auditory information. The hippo- the senses, is labeled in yellow. And the occipital lobe, responsible for vision, is labeled in pink.
campus consists of curved structures
lying beneath the cerebral cortex; it ments like blinking and focusing, and over half the brain’s neurons. Like the
is a region of the temporal lobes that trigger reflexes to sounds. An example cerebrum, the cerebellum is deeply
encodes new memories. Another deep is the startled jump when you are sur- folded, divided into two hemispheres,
structure within each temporal lobe, prised by a loud noise. Other regions and carries out a variety of functions.
the amygdala, integrates memory of the midbrain inhibit unwanted For example, it coordinates voluntary
and emotion. body movements and help coordinate movements and helps the brain learn
The hippocampus and amygdala sensory input and motor output to new motor skills. It also has roles in
are part of the limbic system, a group manage the fine motor control that spatial and temporal perception. A
of structures deep within the brain enables you to write with a pen or play patient with cerebellar damage might
that help regulate our emotion and a musical instrument. have a jerky, arrhythmic gait or might
motivation. Other parts of the limbic Some of these regions — along be unable to accurately touch his
system include the thalamus, which with parts of the forebrain — form a finger to his nose.
integrates sensory information and collection of structures called the basal Below the cerebellum is the pons,
relays it to other parts of the brain, and ganglia, which helps regulate complex which influences breathing and pos-
the hypothalamus, which sends hor- body movements. ture. Another part of the hindbrain,
monal signals to the rest of the body The hindbrain plays roles in glu- the medulla, carries nerve pathways
through the pituitary gland. These cose regulation and sleep and includes connecting the brain to the spinal cord
structures, together with the cerebral several regions that help control move- and contains neural networks that help
cortex, make up the forebrain. ment. The cerebellum, tucked under- control basic functions like swallow-
The midbrain sits beneath the neath the occipital lobe at the very ing, heart rate, and breathing. Together,
thalamus. It includes distinct groups back of the brain, is the second-largest the midbrain, pons, and medulla
of neurons that coordinate eye move- part of the brain in volume, containing make up the brainstem.

1 Brain Basics
Brain Evolution expanded even further, packing new representation of the outside world.
It’s hard to believe that our neurons into layers and folds gen- The image is even further refined as
complex human brain evolved erating more complex tissues with signals are sent down two parallel
from a simple tube. The earliest increased processing power. processing streams. In one stream,
vertebrates probably had brains much neurons in the temporal lobe recognize
like the one in the modern lancelet NEURAL NETWORKS and identify objects; in the other,neu-
Amphioxus — little more than a wide Information moves from one rons in the parietal lobe detect the
spot in the hollow nerve cord running region of your brain to spatial location of those objects. And
down its back. But while the lancelet’s another via chains of neurons that that’s only the visual input from the
brain looks simple, it still contains can transmit signals over long dis- film! New technologies that allow us to
specialized regions where neurons tances. When the nerve fibers of look with increasing detail at the brain
process specific kinds of information, region-spanning neurons form distinct regions being activated as we perform
like the presence of light or the chemi- bundles, these are called nerve tracts. different functions are giving us in-
cals drifting through the water. In its Examples of major nerve tracts include creasing insight into the fine regions of
early development, the human brain the corpus callosum (the thick bundle the brain used for specific tasks.
began as a simple tube, and even today of neurons connecting your left and
it is divided into the same kinds of right cerebral hemispheres) and the Network Activity
regions as the brains of our ancestors. smaller anterior commissure that Creates Brain Waves
In early vertebrates, the “brain” transmits signals between the left The visual cortex also sends sig-
end of the nerve cord developed and right temporal lobes. nals back to the thalamus to become
three distinct bulges as neurons were A group of nerve tracts connect- integrated with other sensory infor-
added, improving processing in sen- ing a series of regions in the brain is mation; this is an example of a “thal-
sory and motor reflex regions. These called a neural network. Neural net- amocortical loop,” a two-way circuit
bulges became the forebrain, the works route signals through the brain that connects the thalamus with parts
midbrain, and the hindbrain. In the along a linear pathway, analyzing and of the cortex and back. As neuronal
forebrain, the region able to detect organizing different types of informa- signals loop through the thalamus
chemicals expanded to form the ol- tion within fractions of a second. and cortex, they produce rhythmic,
factory bulbs, and with the evolution Have you ever wondered what oscillating, electrical patterns that can
of image-producing eyes, light-sens- happens in your brain when you watch be detected with an electroencephalo-
ing regions expanded and began a movie? Your brain turns a panoply graph (EEG). These signals are com-
processing more complex visual sig- of moving shapes into recognizable monly called brain waves. There are
nals. The cerebellum appeared as the characters and scenery. The process four distinct types, each recognized
hindbrain and expanded the regions begins with photoreceptors, cells in by its characteristic shape on an EEG
that control escape movements and the retina that trigger electrical signals display or printout.
orient the body in space. Both these in response to specific wavelengths Your awake brain typically produc-
functions are far more important to of light. Once those signals reach the es alpha waves and beta waves. Alpha
an actively swimming fish than to a optic nerve, they travel through the waves originate mainly in the parietal
sedentary lancelet buried in the sand. optic tract to the thalamus, where and occipital lobes when your brain
Regions that could rapidly process neurons respond to the shape, color, or is relaxed and eyes are closed, and are
visual and auditory information and movement of objects on the screen and characterized by frequencies between
trigger appropriate escape, feeding, or pass their signals to the primary visual 8 and 13 Hz. (The Hertz is a mea-
mating behaviors also expanded in ver- cortex in the occipital lobe, at the back sure of frequency; 1 Hz = 1 cycle per
tebrates. Over time, those new types of the brain. Neurons in the primary second.) Beta waves are somewhat
of neurons made the forebrain balloon visual cortex, in turn, detect the edges faster, with frequencies ranging from
out, forming the cerebral hemispheres. of objects within the field of vision 14 to 30 Hz. Beta waves are typically
In early mammals, cortical tissues in and integrate the signals from each produced by the frontal and parietal
the cerebrum and the cerebellum eye, creating a three-dimensional regions of your brain when it processes

Brain Basics 1
sensory input or concentrates on a works provide feedback that helps NEURAL CIRCUITS
task. Theta waves and delta waves are integrate sensory and motor signals. Each region of your brain
typical of sleep. Theta waves are slower For example, the brain’s basal ganglia analyzes only a specialized
than alpha waves, ranging from 4 to are part of a feedback loop that takes subset of all the information that is
7 Hz, while delta waves, which occur information from cortical areas that received, but all regions use the same
during deep sleep, are very slow, with elicit movement and produces signals basic mechanism to process informa-
frequencies less than 3.5 Hz. Alpha that feed back to the cortex to excite tion. When signals arrive at a brain
and delta waves are typically of higher or inhibit specific movements. Loops region, they engage local neural
amplitude (stronger) than beta or theta that connect the brainstem and the circuits — interconnected neurons
waves but, when measured with elec- cerebellum also influence the timing that turn entering signals into output
patterns that can be sent to other
parts of the brain.
The cerebral cortex is packed
with neural circuits. Neurons are
Neurons are organized into a

organized into a stack of distinct
layers that span the thickness of the
cortex like shelves in a bookcase.
Circuits are arranged in columns, as
stack of distinct layers that span each neuron forms connections with
the thickness of the cortex like cells in the layers above and below.
The neurons in a column form a
shelves in a bookcase. single chain, and signals that enter
the circuit travel down that chain
from one neuron to the next. Each
time the signal is fed forward, it is
transformed in some way, building
trodes on your scalp, all these signals and strength of motor signals; some outputs that encode complex infor-
are in the microvolt range: 20–200 μV of these loops incorporate tracts mation — so you can recognize
for alpha and delta waves, and 5-10 from the cerebral cortex that en- your grandmother’s face in a crowd
μV for beta and theta waves. able environmental and emotional or plan where to run to catch a
context to influence your body’s thrown ball.
Neural Networks Organize movements. Networks that loop the Neuroscientists think each
and Integrate Information hippocampus into sensory cortex column in the cortex is dedicated
Your brain and spinal cord con- pathways help your brain analyze to one very specific processing task.
tain many distinct neural networks. whether environmental signals are But a column’s final output can be
These include spinal tracts — chains familiar or are part of a new situa- influenced by the activity of nearby
of neurons that pass signals through tion. Related networks linking the circuits. Every neuron in a circuit
the brainstem and the spinal cord. hippocampus to the thalamus and has other connections to neurons in
Signals either travel upward from hypothalamus allow your memory neighboring columns. Since every
sensory receptors in skin and mus- to influence conscious behavior as neuron behaves like a microprocessor,
cles to the thalamus and parts of the well as unconscious physiological summing all the signals it receives
cortex that interpret touch and pres- responses. Reflex loops are circuits before sending one of its own, the
sure; or they travel downward from eliciting action well before thoughts; strength of signals from neighbor-
brain regions that induce movement, these actions are controlled locally by ing circuits can dynamically shift
passing through the medulla and information going in and out of the a neuron’s response. This dynamic
spinal cord before projecting to the spinal cord or subcortical regions of organization may help the brain react
body’s muscles. Other neural net- the brain, and never reach the cortex. flexibly to different situations.

1 Brain Basics
Excitatory and
Inhibitory Neurons
Individual neurons are either
excitatory or inhibitory. The majority
of neurons in your brain — about
80 percent of them — are excitatory,
sending signals that push their neigh-
bors toward firing. In many parts of
the cerebral cortex, the most common
type of excitatory neuron is the pyra-
midal cell, named for its cone-shaped
cell body. Each pyramidal cell has two
sets of branched dendrites — one set
at the apex and another set of shorter
dendrites at the base — that collect
signals from neurons in every layer
of the cortex. A multi-branched axon
Mariana Ruiz Villarreal
sends a single electrical signal to mul-

tiple destinations. The 20 percent of
your brain’s neurons that are inhibitory
send signals that suppress the activity This is the neuron, the building block of the nervous system. Neurons come in many shapes
of neighboring neurons and regulate and sizes, but most have some basic features. The cell body contains structures such as the
nucleus. Dendrites, the arms extending from the cell body, receive signals from other neurons at
the activity of a circuit.
junctions called synapses. The neuron sends signals via the axon, a long cable that ends with
Every neural circuit contains both the axon terminals. The axon terminals release chemical messengers called neurotransmitters.
excitatory and inhibitory neurons.
Neurons that pass signals forward simultaneously send inhibitory signals the neuron’s nucleus and most of its
through a circuit and eventually send to adjacent columns, reducing their cytoplasm, along with molecular
outputs to other parts of the brain activity. In feedback inhibition, machinery for building and transport-
tend to be excitatory, while inhibitory however, neurons send signals to their ing proteins critical to the cell’s
neurons are typically local and often downstream excitatory neighbors and function. Dendrites are branched
loop their responses back to earlier to interneurons that reach back and projections that extend from the cell
segments of a circuit. The interplay inhibit preceding layers of the same body and collect incoming signals
between these signals in a circuit seems circuit. Both are examples of recurrent from other neurons. The neuron’s
to be important in learning, tuning neural networks, in which neurons electrical signals travel down its axon
and smoothing the signals sent to the inside interconnected circuits send — another extension from the cell
body and other parts of the brain. feedback signals to one another. body that may branch before ending in
Seizure disorders like epilepsy could be axon terminals, where the signal is
caused by imbalances in the activity of NEURONS AND GLIA passed across a synapse to other cells.
excitatory and inhibitory neurons. The functional unit of neural In some neurons, axons are only a
Within circuits, neurons can be circuits and networks is the fraction of a centimeter long; in others,
organized in a number of different neuron, a specialized cell that can they may extend more than a meter.
input architectures, each affecting how transmit electrical signals to other Neurons are associated with sup-
a circuit manages information. In a nerve cells, muscles, or glands. Neu- port cells called glia. Neuroscientists
feed-forward inhibitory circuit, inhib- rons come in a broad range of shapes have long believed that glia outnumber
itory interneurons connect neighbor- and sizes, but all of them have a cell neurons by 10:1 (or more). However,
ing neural circuits in such a way that body, dendrites, and an axon. The cell recent investigations suggest that in
excitatory signals in one column body, also called the soma, contains some regions of the brains of humans

Brain Basics 1
and other primates, that ratio is closer (hyperpolarized) by opening ion signals can’t directly impact the next
to 1:1. However, the ratio of glia to channels in the dendrites. If the sum neuron; rather, chemical signals called
neuron from region to region varies of all the signals at the dendrites rises neurotransmitters cross the synapse. This
considerably. The central nervous sys- to match the membrane’s threshold process is called neurotransmission.
tem contains four main types of glial voltage, a series of voltage-sensitive ion When an action potential arrives
cells: astrocytes, microglia, ependymal channels opens automatically, triggering at the axon terminal, the voltage
cells, and oligodendrocytes. Astrocytes an electrical impulse called an action change triggers ion channels in the
form a network inside the brain that potential, which moves down the axon membrane to open, which lets calci-
regulates ion concentrations around towards the next neuron in the circuit. um ions flow into the cell. When the
neurons, provides them with nutrients, calcium ions bind to packages of neu-
and helps regulate the formation of SYNAPSES AND rotransmitter molecules called synaptic
new connections between neurons. NEUROTRANSMISSION vesicles, the vesicles fuse with the cell
Microglia are the main “immune cells” Signals are passed from one membrane at the axon terminal and
of the brain. They function mainly neuron to the next at junctions empty their contents into the synap-
as phagocytes — helping protect the called synapses. In most circuits, a tic cleft. Afterwards, pieces of axon
brain from infections and cellular synapse includes the end of an axon, the terminal membrane cycle back into the
damage — but can also regulate the dendrite of an adjacent neuron, and a soma as new vesicles, which are refilled
formation of new neuronal connec- space between the two called the with neurotransmitter molecules.
tions. Ependymal cells make the cere- synaptic cleft. Amazingly, this separa- Many substances act as nero-
brospinal fluid that cushions the brain tion between neurons was only verified transmitters, including amino acids,
inside the skull, and oligodendrocytes (by electron microscopy) in the 1950s. gases, small organic chemicals, and
improve neuron function by wrapping The cleft is wide enough that electrical short peptides. Neurons can synthesize
axons in a fatty sheath called myelin.
Ion Channels and

Action Potentials
Ions are electrically charged atoms
that can only cross a neuron’s cell
membrane through tunnel-like pro-
teins called ion channels. These
tunnel-like proteins act like gates, al-
lowing some ions to enter or leave the
cell, but keeping others out. Ions that
enter or leave the cell change the volt-
age difference across the membrane.
This change in voltage influences the
Ferreira, et al. The Journal of Neuroscience, 2015.
neuron’s likelihood of generating an

electrical signal.
In mammals, the voltage difference
across the membrane of a resting neu-
ron is around -70 millivolts (mV), more
negative inside the cell than on its outer
surface. That membrane potential is
affected by signals arriving from other
neurons in its circuit, which can make Dendrites — the arms extending from a neuron’s cell body — receive information from other
neurons at sites called synapses. Each dendrite can have thousands of synapses, which
the membrane potential less negative together form complex circuits that govern brain function. The synapses on this mouse
(depolarized) or more negative neuron are labeled in yellow and red.

1 Brain Basics
small non-peptides like dopamine or channels, altering the voltage across time. Once they detach, the ion
acetylcholine inside the axon termi- the postsynaptic membrane. Local channels return to their resting state
nal. But an axon terminal doesn’t glial cells (astrocytes) mop up any ex- and stop altering the charge across
contain the molecular machinery for cess neurotransmitters at the synapse. their membrane. The neurotrans-
building proteins, so peptide-based This process prevents them from mitters are either broken down or
neurotransmitters are built in the continuously activating receptors. reabsorbed by the axon terminal in a
ribosome-rich space of the cell body. There are two broad types of process called reuptake.
Vesicles containing neurotransmit- receptors on the postsynaptic mem- The excitatory and inhibitory
ter “cargos” bud off from the wall brane. In an ionotropic receptor, a neurons described above can be
identified by the specific neurotrans-
mitters that they make. Excitatory
neurons make neurotransmitters that
open ion channels that depolarize
Many different molecules act

the dendrite’s membrane; inhibitory
neurons make neurotransmitters that
hyperpolarize it. The brain’s most
common excitatory neurotransmitter
as neurotransmitters, and each one is glutamate; the brain’s most com-
fits into specific receptors like a mon inhibitory neurotransmitter is
gamma-aminobutyric acid (GABA).
key fits a lock. Glutamate is an amino acid used
as a neurotransmitter by approximate-
ly half the excitatory synapses in the
brain. It can bind to several types of
ionotropic receptors; the most im-
of the Golgi apparatus — the cell’s neurotransmitter binds directly to portant of these are AMPA receptors
protein-packaging organelle — then part of an ion channel. The chan- and NMDA receptors. When acti-
bind to proteins called kinesins that nel is normally closed; the receptor vated, the action of AMPA receptors
work their way down the axon along protein changes its shape when the is fast and brief; NMDA receptors
microtubules, filamentous parts of the neurotransmitter attaches, widen- activate more slowly, particularly in
cellular skeleton. ing the tunnel in the center of the response to waves of multiple action
After neurotransmitters are ion channel so that ions can move potentials. Interactions between these
released from an axon terminal, through. Metabotropic receptors are receptors appear to be important in
they drift across the synaptic cleft more complex. The receptor and the learning and memory.
until they reach the outer surface ion channel are different proteins lo- GABA is the brain’s most im-
of the dendrite, a region that looks cated at a distance from one another, portant inhibitory neurotransmitter.
thick or dense in highly magnified but they are linked by a cascade of It binds to two groups of receptors;
images. This region, the postsyn- biochemical steps that are triggered one group is ionotropic, the other
aptic density, has a high concentra- when a neurotransmitter binds to the metabotropic. Ionotropic GABA
tion of neurotransmitter receptors. receptor. This response is less rapid receptors have ion channels that let
Many different molecules act as and activates a series of events inside negatively charged chloride ions enter
neurotransmitters, and each one fits the postsynaptic cell. The result may the cell. Metabotropic GABA recep-
into specific receptors like a key fits be opening an ion channel some dis- tors open ion channels that release
a lock. Receptors are linked to ion tance away or activating other intra- potassium ions. In both instances, ion
channels in such a way that, when cellular molecules. movement pushes membrane poten-
neurotransmitter molecules dock on Neurotransmitter molecules only tial downward and inhibits a neuron
their receptors, they open those bind to their receptors for a short from firing.

Brain Basics 1
RECEPTORS AND NEURONS, GENES, and are associated with open, unfolded
MOLECULAR SIGNALING AND GENE EXPRESSION chromatin, while unexpressed genes
Neurons have receptors for many By this point, it should be clear are typically in tightly packed regions.
molecules that can change the way that neurons inside the brain can differ Chemical changes that tighten or
they function. These molecules include in appearance and function. They can spread out chromatin complexes can,
hormones, which send the brain produce different types of neurotrans- respectively, shut down or activate the
specific cues about the condition and mitters, determining whether their genes on that segment of DNA. These
activity of distant tissues in the body; signals have excitatory or inhibitory changes are reversible, giving neurons
neuromodulators such as the endo- effects in their circuits. They can have flexibility to alter the genes they
cannabinoids, cannabis-like chemicals different assortments of neurotrans- express in response to hormonal cues
that seem to suppress neurotransmit- mitter receptors, determining the cells’ and environmental changes.
ter release; and prostaglandins, small sensitivity to the effects of specific The genes that affect neuron
lipids that change the brain’s response neurotransmitters. And, in their cell structure and function can also differ
(increasing pain sensitivity) to pain membranes, neurons possess different between individuals. Gene variants
and inflammation. combinations of receptors capable of or alleles reflect differences in the
Individual neurons have receptors detecting neuromodulators that influ- nucleotide sequences that make up
for different subsets of hormones and ence neuronal behavior — for exam- a gene. While different alleles code
neuromodulators. In each case, these ple, hormones such as vasopressin, for forms of the same protein, the
molecules are signals that trigger a estradiol, or cortisol. variants can produce structural dif-
series of chemical reactions inside the All cells in your body, including ferences that affect their function. An
cell. The process starts when one of neurons, contain the same DNA allele might code for a version of an
these molecules binds to its specific housing the same genes. Differences enzyme that is less effective than the
receptor. If the receptor is on the among your neurons result from dif- usual version, and specific alleles of
surface of the cell, the bound molecule ferences in which genes direct cellular some genes can even cause neurolog-
changes the receptor’s shape across the activities, a process called gene expres- ical diseases. For example, Tay-Sachs
cell membrane and starts a chain of in- sion. Each cell (or cell type) builds disease, a fatal degenerative neurolog-
tracellular reactions. This signal trans- proteins from a slightly different ical condition, is caused by muta-
duction pathway ultimately modifies subset of genes in its genetic code, the tions in a gene that codes for part
neuronal function, either by shifting same way different children will build of a fat-metabolizing enzyme called
the cell’s ion balance or by changing different structures from the same beta-hexosaminidase A. Because the
the activity of specific enzymes. starting set of Lego blocks. variant enzyme is poor at breaking
If a molecule can diffuse through The mechanisms causing neu- down specific fats, these build up in
the cell membrane — as occurs with rons to express some genes and not neurons and become toxic. There
steroid hormones like estradiol or cor- others are currently an area of intense are many cases where small changes
tisol — its receptor might be a protein research. Many of these mechanisms in genetic sequence affect how our
inside the neuron’s soma. When the depend on chemical changes to brain can function, and in the next
hormone binds to its receptor, the com- chromatin, the complex of protein 10 years — with our capacity to se-
plex can transform into a transcription and DNA that compactly packages quence a person’s entire genome now
factor that is capable of entering the cell the long DNA molecule inside the possible — we will be able to move
nucleus, binding to specific genes and nucleus. Genes that a cell is using to much closer to understanding the
changing their activity. build proteins need to be accessible genetic basis of brain disorders.

CHAPTER
2
Senses & Y
ou can think of your sense or-
gans as the brain’s windows on
the external world. The world
itself has no actual images, sounds,
Perception tastes, and smells. Instead, you are sur-

rounded by different types of energy
and molecules that must be translated
into perceptions or sensations. For this
extraordinary transformation to work,
your sense organs turn stimuli such
as light waves or food molecules into
electrical signals through the process of
transduction. These electrical messages
are then carried through a network of
cells and fibers to specialized areas of
your brain where they are processed
and integrated into a seamless percep-
tion of your surroundings.
VISION
Vision is one of your most compli-
cated senses, involving many processes
that work simultaneously enabling you
to see what is happening around you.
It is no surprise, then, that the visual
system involves about 30 percent of
humans’ cerebral cortex — more than
any other sense does. Vision has been
studied intensively, and we now know
more about it than any other sensory
system. Knowledge of how light ener-
gy is converted into electrical signals
comes primarily from studies of fruit
flies (Drosophila) and mice. Higher-
level visual processing has mostly
been studied in monkeys and cats.
In many ways, seeing with your
eyes is similar to taking pictures with
an old-fashioned camera. Light passes
through the cornea and enters the eye
through the pupil. The iris regulates
how much light enters by changing
the size of the pupil. The lens then
bends the light so that it focuses on
the inner surface of your eyeball, on
a sheet of cells called the retina. The
rigid cornea does the initial focusing,
Senses & Perception 2
but the lens can thicken or flatten to on the other hand, pick up fine detail for reading and driving. In the United
bring near or far objects into better and color, allowing you to engage in States and other developed countries,
focus on the retina. Much like a cam- activities that require a great deal of death or degeneration of photoreceptors
era capturing images on film, visual visual acuity. The human eye contains in the macula, called macular degener-
input is mapped directly onto the three types of cones, each sensitive to ation, is a leading cause of blindness in
retina as a two-dimensional reversed a different range of colors (red, green, people older than 55.
image. Objects to the right proj- or blue). Because their sensitivities Neurons in each of the three layers
ect images onto the left side of the overlap, differing combinations of the of the retina typically receive inputs
retina and vice versa; objects above three cones’ activity convey informa- from many cells in the preceding layer,
are imaged at the lower part and vice tion about every color, enabling you but the total number of inputs varies
versa. After processing by specialized to see the familiar color spectrum. In widely across the retina. For example,
cells in several layers of the retina, that way, your eyes resemble computer in the macular region where visual
signals travel via the optic nerves to monitors that mix red, green, and blue acuity is highest, each ganglion cell
other parts of your brain and undergo levels to generate millions of colors. receives input (via one or more inter-
further integration and interpretation. Because the center of the retina neurons) from just one or very few
contains many more cones than other cones, allowing you to resolve very fine
The Three-Layered Retina retinal areas, vision is sharper here than details. Near the margins of the retina,
The retina is home to three in the periphery. In the very center of however, each ganglion cell receives
types of neurons — photo- the retina is the fovea, a small pitted signals from several photoreceptor
receptors, interneurons, and ganglion area where cones are most densely cells. This convergence of inputs
cells — which are organized into packed. The fovea contains only red explains why your peripheral vision
several layers. These cells communicate and green cones and can resolve very is less detailed. The portion of visual
extensively with each other before fine details. The area immediately space providing input to a single gan-
sending information along to the brain. around the fovea, the macula, is critical glion cell is called its receptive field.
Counterintuitively, the light-sensitive
photoreceptors — rods and cones
— are located in the most peripheral
layer of the retina. This means that after
entering through the cornea and lens,
light travels through the ganglion cells
and interneurons before it reaches the
photoreceptors. Ganglion cells and
interneurons do not respond directly to
light, but they process and relay
information from the photoreceptors;
Ward, et al. The Journal of Neuroscience, 2014.
the axons of ganglion cells exit the

retina together, forming the optic nerve.
There are approximately 125
million photoreceptors in each human
eye, and they turn light into electrical
signals. The process of converting one
form of energy into another occurs in
most sensory systems and is known as
transduction. Rods, which make up Here, in the back of the eye, is one of the first stops visual information makes on its way to
about 95 percent of photoreceptors the brain. In this image of a mouse retina, axons of nerve cells are labeled in yellow. They
extend through a small opening in the back of the eye — labeled in black — through the
in humans, are extremely sensitive, al- optic nerve to higher vision centers. The axons must penetrate another layer of cells known
lowing you to see in dim light. Cones, as astrocytes, labeled in blue, that provide nutritional support to the retina.

2 Senses & Perception
How Is Visual
Information Processed?
Every time you open your
eyes, you distinguish shapes,
colors, contrasts and the speed and
direction of movements. You can easily
distinguish your coffee mug from the
peanut butter jar in front of you. You
can also tell that the tree outside the
window stands still and the squirrel is
Miquel Perelló Nieto.
scurrying up the tree (not vice versa).
But how is a simple two-dimensional
retinal image processed to create such
complex imagery?
Vision begins with light. The light bouncing off an object passes through the optical lens and
Visual processing begins with
hits the retina at the back of the eye. Receptors in the retina transform light into electrical
comparing the amounts of light hit- signals that carry information to the vision processing centers in the brain.
ting small, adjacent areas on the retina.
The receptive fields of ganglion cells information from the left side of the of cells, new processing streams pass
“tile” the retina, providing a complete retinas of both eyes continue together the information along to other parts
two-dimensional representation (or on the left side of the brain; informa- of the visual cortex. As visual infor-
map) of the visual scene. The recep- tion from the right side of both retinas mation from the primary visual cortex
tive field of a ganglion cell is activated proceeds on the right side of the brain. is combined in other areas, receptive
when light hits a tiny region on the Visual information is then relayed fields become increasingly complex and
retina that corresponds to the center of through the lateral geniculate nucleus, selective. Some neurons at higher levels
its field; it is inhibited when light hits a region of the thalamus, and then to of processing, for example, respond
the donut-shaped area surrounding the primary visual cortex at the rear only to specific objects and faces.
the center. If light strikes the entire of the brain. Studies in monkeys suggest that vi-
receptive field — the donut and its sual signals are fed into several parallel
hole — the ganglion cell responds only Visual Cortex: but interacting processing streams. Two
weakly. This center-surround antago- Layers, Angles, and Streams of these are the dorsal stream, which
nism is the first way our visual system The primary visual cortex, a thin heads up toward the parietal lobe, and
maximizes the perception of contrast, sheet of neural tissue no larger than a the ventral stream, which heads down
which is key to object detection. half-dollar, is located in the occipital to the temporal lobe. Traditionally,
Neural activity in the axons of lobe at the back of your brain. Like these streams were believed to carry
ganglion cells is transmitted via the the retina, this region consists of many out separate processing of unconscious
optic nerves, which exit the back of layers with densely packed cells. The vision, which guides behavior and
each eye and travel toward the back of middle layer, which receives messages conscious visual experiences. If you see
the brain. Because there are no photo- from the thalamus, has receptive fields a dog running out into the street, the
receptors at this site, the exit point of similar to those in the retina and can ventral or “What” stream would inte-
the optic nerve results in a small “blind preserve the retina’s visual map. Cells grate information about the dog’s shape
spot” in each eye, which our brains above and below the middle layer have and color with memories and experi-
fortuitously “fill in” using information more complex receptive fields, and ences that let you recognize the dog as
from the other eye. On their way to they register stimuli shaped like bars or your neighbor’s. The dorsal or “Where”
the brain, signals travel along nerve edges or with particular orientations. stream would combine various spatial
fibers from both eyes which first For example, specific cells can respond relationships, motion, and timing to
converge at a crossover junction called to edges at a certain angle or moving in create an action plan, but without a
the optic chiasm. Those fibers carrying a particular direction. From these layers need for conscious thought. You might

shout out “Stop!” without thinking. they start to favor one eye and often tects, such as a sound’s pitch, loudness,
Ongoing research now questions this lose vision in the other. Vision can be duration, and location. Your auditory
strict division of labor and suggests that restored in such cases, but only if the system analyzes complex sounds, break-
crosstalk between streams may actually child is treated at a young age; beyond ing them into separate components or
create a conscious experience. Clearly, the age of 8 or so, the blindness frequencies, as a result, you can follow
in recognizing an image the brain becomes permanent. Until a few particular voices in a conversation or
extracts information at several stages, decades ago, ophthalmologists waited instruments as you listen to music.
compares it with past experiences, and until children were 4 years old before
passes it to higher levels for processing. operating to align the eyes, prescribing Can You Hear Me Now?
exercises or using an eye patch. Now Whether it’s the dreaded alarm in
Eyes Come in Pairs strabismus is corrected well before age 4, the morning, the ringtone on your cell
Seeing with two eyes, called binoc- when normal vision can still be restored. phone, or your favorite jogging music,
ular vision, allows you to perceive depth Loss of function or death of hearing involves a series of steps that
or three dimensions, because each eye photoreceptors appears to lie at the convert sound waves in the air into
sees an object from a slightly different heart of various disorders that cause electrical signals that are carried to the
angle. This only works if the eyes’ blindness. Unfortunately, many are brain by nerve cells. Sound in the form
visual fields overlap and if both eyes are difficult to treat. Extensive genetic of air pressure waves reaches the pin-
equally active and properly aligned. A studies and the use of model organisms nae of your ears, where the waves are
person with crossed eyes, a condition have identified a variety of genetic funneled into each ear canal to reach
called strabismus, misses out on much defects that cause people to go blind, the eardrum (tympanic membrane).
depth perception. Information from making it possible to design gene or The eardrum vibrates in response to
the perspective of each eye is preserved stem cell therapies that can recover these changes in air pressure, send-
all the way to the primary visual cortex photoreceptors. Researchers are working these vibrations to three tiny,
where it is processed further. Two eyes ing on potential treatments for genetic sound-amplifying bones in the middle
also allow a much larger visual field blindness, and gene therapies have ear: the malleus (hammer), incus (an-
to be mapped onto the primary visual already enabled some patients with loss vil), and stapes (stirrup). The last bone
cortex. Because some of the nerve fibers of central vision (macular degenera- in the chain (the stapes) acts like a tiny
exiting each eye cross over at the optic tion) or other forms of blindness to see piston, pushing on the oval window,
chiasm, signals from the left visual field better. Work is also underway to send a membrane that separates the air-
end up on the right side of the brain electrical signals directly to the brain filled middle ear from the fluid-filled,
and vice versa, no matter which eye via ganglion cells rather than attempt- snail-shell-shaped cochlea of the inner
the information comes from. A similar ing to restore lost photoreceptors, an ear. The oval window converts the
arrangement applies to movement and approach very similar to the use of mechanical vibrations of the stapes
touch. Each half of the cerebrum is cochlear implants to treat deafness. into pressure waves in the fluid of the
responsible for processing information cochlea, where they are transduced
from the opposite side of the body. HEARING into electrical signals by specialized
Hearing is one of your most receptor cells (hair cells).
Treating Visual Disorders important senses, alerting you to an ap-
Many research studies using proaching car and telling you where it’s From Pressure
animals have provided insights coming from long before it comes into Wave to Electrical Signal
into treatment of diseases that affect sight. Hearing is also central to social An elastic membrane, called
eyesight. Research with cats and interactions. It allows you to communi- the basilar membrane, runs
monkeys has helped us find better cate with others by processing and inter- along the inside of the cochlea like a
therapies for strabismus. Children with preting complex messages in the form of winding ramp, spiraling from the
strabismus initially have good vision in speech sounds. Like the visual system, outer coil, near the oval window, to
each eye but, because they cannot fuse your hearing (auditory) system picks up the innermost coil. The basilar mem-
the images coming from both eyes, several qualities of the signals it de- brane is “tuned” along its length to

different frequencies (pitches). When where different auditory neurons Treating Hearing Loss
fluid inside the cochlea ripples, the respond to different frequencies. Some Loss of hair cells is responsible for
membrane moves, vibrating to higher- cortical neurons, however, respond to the majority of cases of hearing loss.
pitched sounds (like the screech of sound qualities such as intensity, Unfortunately, once they die, hair
audio feedback) near the oval window duration, or a change in frequency. cells don’t regrow. Current research is
and to lower-pitched sounds (like a Other neurons are selective for complex therefore focusing on how inner ear
bass drum) in the center. sounds, while still others specialize in structures like hair cells develop and
Rows of small sensory hair cells various combinations of tones. At function, exploring new avenues for
are located on top of the vibrating higher levels, beyond the primary treatment that could eventually involve
basilar membrane. When the mem- auditory cortex, neurons are able to neurogenesis with the goal of replacing
brane moves up and down, micro- process harmony, rhythm, and melody, damaged hair cells.
scopic hair-like stereocilia extending and combine the types of auditory
from the hair cells bend against an information into a voice or instrument TASTE AND SMELL
overlying structure called the tectorial that you can recognize. The senses of taste (gustation) and
membrane. This bending opens small Although sound is processed on smell (olfaction) are closely linked and
channels in the stereocilia that allow both sides of the brain, the left side is help you navigate the chemical world.
ions in the surrounding fluid to rush typically responsible for understanding Just as sound is the perception of air
in, converting the physical movement and producing speech. Someone with pressure waves and sight is the percep-
into an electrochemical signal. Hair damage to the left auditory cortex tion of light, smell and taste are your
cells stimulated in this way then excite (particularly a region called Wernicke’s perceptions of tiny molecules in the air
the auditory nerve, which sends its area), as from a stroke, is able to hear and in your food. Both of these senses
electrical signals on to the brainstem. a person speak but no longer under- contribute to how food tastes, and
The next stop for sound process- stands what is being said. both are important to survival, because
ing is the thalamus, the brain’s relay
station for incoming sensory informa-
tion, which then sends the information
into the auditory part of the cerebral
cortex. Several thousand hair cells are
positioned along the length of the bas-
ilar membrane. Each hair cell responds
most strongly to just a narrow range
of sound frequencies, depending on
how far along the cochlea it is located.
Thus, each nerve fiber connecting with
the hair cells is tuned to very specific
frequencies and carries this informa-
tion into the brain.
Chittka, et. al. PLoS Biology, 2005.
Making Sense of Sound

On the way to the cortex, the
brainstem and thalamus use
the information from both ears to
compute a sound’s direction and
location. The frequency map of the
basilar membrane is maintained Sound waves — vibrations in the air caused by the sound’s source — are picked up by the outer
ear and funneled down the auditory canal to the ear drum. There, the malleus (hammer) transfers
throughout, even in the primary vibrations to the incus (anvil) and then onto the stapes. Hair cells in the cochlea convert the infor-
auditory cortex in the temporal lobe, mation in these vibrations to electrical signals, which are sent to the brain via the cochlear nerve.

ating a distinct activity pattern. This

“signature” pattern of activity is then
Braubach, et al. The Journal of Neuroscience, 2013.

transmitted to the olfactory bulb and
Ma, et al. The Journal of Neuroscience, 2009.

on to the primary olfactory cortex
located on the anterior surface of the
temporal lobe. Olfactory information
then passes to nearby brain areas,
where odor and taste information
are mixed, creating the perception of
flavor. Recent research suggests that
Your tongue’s receptors, called taste buds, The olfactory bulb is a structure in the people can identify odors as quickly
transform information about tastes and send forebrain responsible for processing smell as 110 milliseconds after their first
them to the brain to be processed into your information. This series of images shows sniff. Interestingly, the size of the
favorite flavors. In this image of a mouse the olfactory bulbs from a zebrafish at
tongue, the axons that connect to these three stages of development. olfactory bulbs and the way neurons
receptors are highlighted in red. are organized can change over time.
As mentioned above, the olfactory
they enable people to detect hazardous glossopharyngeal, and vagus nerves bulbs in rodents and primates (includ-
substances they might inhale or ingest. — to taste regions in the brainstem. ing humans) are one of the few brain
The cells processing taste and smell are The impulses are then routed through regions able to generate new neurons
exposed to the outside environment, the thalamus to the gustatory cortex in (neurogenesis) throughout life.
leaving them vulnerable to damage. the frontal lobe, and insula where
Because of this, taste receptor cells regu- specific taste perceptions are identified. Combining Taste and Smell
larly regenerate, as do olfactory receptor Taste and smell are separate senses
neurons. In fact, olfactory neurons are From Molecules to Smell with their own receptor organs. Yet,
the only sensory neurons that are con- Odors enter the nose on air we notice their close relationship when
tinually replaced throughout our lives. currents and bind to special- our nose is stuffed up by a cold and
ized olfactory cells on a small patch of everything we eat tastes bland. It seems
From Molecules to Taste mucus membrane high inside the nasal like our sense of taste no longer works,
Our ability to taste foods cavity. Axons of these sensory neurons but the actual problem is that we
depends on the molecules set enter the two olfactory bulbs (one for detect only the taste, not taste and
free when we chew or drink. These each nostril) after crossing through smell combined. Taste sense itself is
molecules are detected by taste (or tiny holes in the skull. From there, the rather crude, distinguishing only five
gustatory) cells within taste buds information travels to the olfactory basic taste qualities, but our sense of
located on the tongue and along the cortex. Smell is the only sensory smell adds great complexity to the
roof and back of the mouth. We have system that sends sensory information flavors we perceive. Human studies
between 5,000 and 10,000 taste buds directly to the cerebral cortex without have shown that taste perceptions are
but start to lose them around age 50. first passing through the thalamus. particularly enhanced when people are
Each taste bud consists of 50 to 100 We have around 1,000 different exposed to matching combinations of
sensory cells that are receptive to one of types of olfactory cells, but can iden- familiar tastes and smells. For example,
at least five basic taste qualities: sweet, tify about 20 times as many smells. sugar tastes sweeter when combined
sour, salty, bitter, and umami (Japanese The tips of olfactory cells are equipped with the smell of strawberries, than
for “savory”). Contrary to common with several hair-like cilia that are when paired with the smell of peanut
belief, all tastes are detected across the receptive to a number of different odor butter or no odor at all. Taste and
tongue and are not limited to specific molecules, and many cells respond to smell information appear to converge
regions. When taste receptor cells are the same molecules. A specific smell in several central regions of the brain.
stimulated, they send signals through will therefore stimulate a unique There are also neurons in the inferior
three cranial nerves — the facial, combination of olfactory cells, cre- frontal lobe that respond selectively to

specific taste and smell combinations.

Some of our sensitivity to taste
and smell is lost as we age, most likely
because damaged receptors and senso-
Hadjab, et al. The Journal of Neuroscience, 2013.

ry neurons are no longer replaced by
new ones. Current research is getting
closer to understanding how stem cells
give rise to the neurons that mediate
smell or taste. With this knowledge,
stem cell therapies might one day be
used to restore taste or smell to those
who have lost it.
In this image, sensory nerve fibers, labeled in red, can be seen in the paw of a developing
mouse embryo. These nerve fibers will become specialized to detect either pressure, pain,
TOUCH AND PAIN temperature, or itch.
The somatosensory system is
responsible for all the touch phones. Very sensitive body areas like distressing. Pain is primarily a warning
sensations we feel. These can include lips and fingertips stimulate much larger signal — a way your brain tells itself
light touch, pressure, vibration, regions of the cortex than less sensitive that something is wrong with the body.
temperature, texture, itch, and pain. parts of the body. The sensitivity of Pain occurs when special sensory fibers,
We perceive these sensations with different body regions to tactile and called nociceptors, respond to stimuli
various types of touch receptors whose painful stimuli depends largely on the that can cause tissue damage. Normally,
nerve endings are located in different number of receptors per unit area and nociceptors respond only to strong or
layers of our skin, the body’s main the distance between them. In contrast high-threshold stimuli. This response
sense organ for touch. In hairy skin to your lips and hands, which are the helps us detect when something is truly
areas, some particularly sensitive nerve most sensitive to touch, touch receptors dangerous. Different types of nocicep-
cell endings wrap around the bases of on your back are few and far apart, tors are sensitive to different types of
hairs, responding to even the slightest making your back much less sensitive. painful stimuli, such as thermal (heat
hair movement. Neurologists measure this sensi- or cold), mechanical (wounds), or
Signals from touch receptors travel tivity using two-point discrimination chemical (toxins or venoms). Interest-
along sensory nerve fibers that connect — the minimum distance between two ingly, these same receptors also respond
to neurons in the spinal cord. From points on the skin that a person can to chemicals in spicy food, like the
there, the signals move upward to the identify as distinct stimuli rather than capsaicin in hot peppers, which might
thalamus and on to the somatosen- a single one. Not surprisingly, acuity is produce a burning pain, depending on
sory cortex, where they are translated greatest (and the two-point threshold your sensitivity. Some types of nocicep-
into a touch perception. Some touch is lowest) in the most densely nerve- tors respond only to chemical stimuli
information travels quickly along my- packed areas of the body, like the fingers that cause itch. A well-known example
elinated nerve fibers with thick axons and lips. By contrast, you can distin- is histamine receptors that are activated
(A-beta fibers), but other information guish two stimuli on your back only if when skin irritation, bug bites, and
is transmitted more slowly along thin, they are several centimeters apart. allergies trigger the release of histamine
unmyelinated axons (C fibers). inside your body. But scientists have
Pain and Itch Signals recently identified other itch-specific
Cortical Maps Pain is both a sensory experi- receptors as well.
and Sensitivity to Touch ence and an emotional experi- When tissue injury occurs, it
Somatosensory information from ence. The sensory component signals triggers the release of various chemicals
all parts of your body is spread onto the tissue damage or the potential for at the site of damage, causing inflam-
cortex in the form of a topographic map damage, and the emotional component mation. This inflammatory “soup”
that curls around the brain like head- makes the experience unpleasant and then triggers nerve impulses that cause

you to continue feeling pain, which pathway). From there, they are relayed a person feels. They also explain why
helps you protect a damaged part of to several areas of the cerebral cortex some people develop chronic pain that
the body. Prostaglandins, for example, that monitor the state of the body and does not respond to regular treatment.
enhance the sensitivity of receptors to transform pain and itch messages into Research shows that endorphins act at
tissue damage, making you feel pain conscious experience. Once aware, the multiple types of opioid receptors in
more intensely. They also contribute to brain has to opportunity to change the brain and spinal cord, which has
a condition called allodynia, in which how it responds to these messages. important implications for pain ther-
even soft touch can produce pain, as on apy, especially for people who suffer
badly sunburned skin. A long-lasting Pain Management from intense chronic pain. For exam-
injury may lead to nervous system Why do different people, ple, opioid drugs can now be delivered
changes that enhance and prolong the when exposed to the same pain to the spinal cord before, during, and
perceived pain, even in the absence stimulus, experience the pain different- after surgery to reduce pain. And
of pain stimuli. The resulting state of ly? How itchy or painful something scientists are studying ways to elec-
hypersensitivity to pain, called neuro- feels obviously depends on the strength trically stimulate the spinal cord to
pathic pain, is caused by a malfunc- of the stimulus, but also on a person’s relieve pain while avoiding the po-
tioning nervous system rather than by emotional state and the setting in tentially harmful effects of long-term
an injury. An example of this condition which the injury occurs. When pain opioid use. Variations in people’s
is diabetic neuropathy, in which nerves messages arrive in the cortex, the brain perceptions of pain also suggest ave-
in the hands or feet are damaged by can process them in different ways. nues of research for treatments that are
prolonged exposure to high blood The cortex sends pain messages to a tailored to individual patients.
sugar and send signals of numbness, region of the brainstem called the It is now clear that no single brain
tingling, burning, or aching pain. periaqueductal gray matter. Through area is responsible for the perception of
its connections with other brainstem pain and itch. Emotional and sensory
Sending and nuclei, the periaqueductal gray matter components create a mosaic of activity
Receiving Messages activates descending pathways that that influences how we perceive pain.
Pain and itch messages make their modulate pain. These pathways also In fact, some treatment methods —
way to the spinal cord via small A-delta send messages to networks that release such as meditation, hypnosis, massag-
fibers and even smaller C fibers. The endorphins — opioids produced by es, cognitive behavioral therapy, and
myelin sheath covering A-delta fibers the body that act like the analgesic the controlled use of cannabis — have
helps nerve impulses travel faster, and morphine. Adrenaline produced in successfully targeted the emotional
these fibers evoke the immediate, sharp, emotionally stressful situations like a component rather than stopping the
and easily identified pain produced, for car accident also works as an analgesic painful stimulus itself. Patients with
example, by a pinprick. The unmyelin- — a drug that relieves pain without a chronic pain still feel the pain, but it
ated C fibers transmit pain messages loss of consciousness. The body’s no longer “hurts” as much. We don’t
more slowly; their nerve endings spread release of these chemicals helps fully understand how these therapies
over a relatively large area and produce regulate and reduce pain by intercept- work, but brain imaging tools have
a dull and diffuse ache or pain sensa- ing the pain signals ascending in the revealed that cannabis, for example,
tion whose origin is harder to pinpoint. spinal cord and brainstem. suppresses activity in only a few pain
Pain and itch signals travel up the Although these brain circuits exist areas in the brain, primarily those that
spinal cord through the brainstem and in everyone, their efficacy and sensi- are part of the limbic system, the
then to the thalamus (the ascending tivity will influence how much pain emotional center of the brain.

CHAPTER
3
Movement H
ave you ever marveled at
the athleticism of a tennis
player as she lands a perfect
serve, or the virtuosity of a pianist
whose fingers dance through a piece
by Rachmaninoff? These are special
and dramatic movements. Yet in our
daily lives, each of us performs a
suite of complex, skilled movements
that are equally remarkable — from
walking and talking, to signing our
names, or sending a text. We even
use our muscles to reveal our current
mood: A smile and a wave are univer-
sally understood.
Movement is such an integral
part of our day-to-day experience that
we take for granted the sophisticat-
ed systems that make these actions
possible. The central nervous system
— brain and spinal cord — directs the
coordinated actions of the hundreds of
muscles that enable us to move. These
actions are refined and strengthened as
we make our way through the world,
adapting to changing circumstances
and practicing, sometimes even im-
proving, our motor skills.
VOLUNTARY MOVEMENTS
To understand how the
nervous system governs
motion, we begin with the muscles,
the structures of the body that
produce movement. Most muscles
attach to the skeleton and span
joints, the sites where two or more
bones come together. The close
relationship of these muscles to the
skeleton gives them their name —
skeletal muscles. Activating muscles
can either flex or extend the joint
that they span. Muscles that bend a
joint, bringing the bones closer
together, are called flexors; muscles
that straighten the joint, increasing
the angle between the bones, are
Movement 3
called extensors. Flexors and exten-

sors work in opposition, so when one
set of muscles contracts, the other
relaxes. For example, bending the
elbow requires contraction of the
biceps (a flexor) and relaxation of the
triceps (an extensor). For such
motions, the muscles that promote
the movement are called agonists,
and those that oppose or inhibit the
movement are antagonists. Skilled,
rapid movements — like throwing a
dart — are started by agonists and
stopped by antagonists, allowing the
limb to accelerate and halt with great
speed and precision. For some move-
ments, agonists and their opposing
antagonists contract at the same time,
which is called co-contraction. These
simultaneous actions can stabilize or
control a movement, such as holding
an object at arm’s length or stabiliz-
ing an immobile joint during
isometric exercises.
Whether flexion or extension,
the movement of all skeletal muscles
is controlled by the central nervous
system. A skeletal muscle is made
up of thousands of individual mus-
cle cells, called muscle fibers. Each
muscle fiber is controlled by a single
alpha motor neuron that originates in
the spinal cord or the brain. However,
each of these alpha motor neurons
can control multiple muscle fibers
(from a few to 100 or more). An al-
pha motor neuron plus all the muscle
fibers it controls form a functional
unit known as a motor unit, the crit-
ical link between the central nervous
The nervous system is divided in two. The central nervous system consists of the brain and
system and skeletal muscles. When
spinal cord. The peripheral nervous system consists of nerves and small concentrations of
motor neurons die — as happens in gray matter called ganglia. The brain sends messages to the peripheral nerves, which control
diseases like amyotrophic lateral the muscles and internal organs.
sclerosis (ALS) — people can lose
their ability to move.
Some muscles act not on joints but
on soft tissue. For example, muscles

3 Movement
in the head and neck enable us to

move our eyes, chew and swallow
food, have conversations, and control
our facial expressions. These muscles
are also controlled by the central
nervous system, and they operate
in much the same way as those that
attach to bones.
INVOLUNTARY
MOVEMENTS
Many types of movement take
place without our conscious
control. Among the simplest and most
fundamental types of involuntary
movements are the reflexes. Reflexes
are relatively stereotyped, automatic
muscle responses to particular stimuli
— think of the rapid withdrawal of
your hand after touching something
hot. These reflexes involve the activa-
tion of sensory receptors in the skin,
the joints, or even in the muscles
themselves. The responses are rapid
and occur without involvement of the
brain or conscious attention. Instead,
they depend on circuits of neurons
located in or near the spinal
cord itself.
One of the best-known reflexes
is the “knee jerk” response, a stretch
(myotatic) reflex that occurs when
a physician strikes the tendon just
below the knee with a small rubber
hammer. This tap produces a slight
stretch of the knee extensor muscle,
which is “sensed” by receptors within
the muscle called muscle spindles.
The spindles sense the extent and
speed of the stretch, and stimu-
late sensory neurons, which send a
barrage of impulses into the spinal
The stretch reflex, as seen at top of the image, occurs when a doctor taps a muscle tendon
to test your reflexes. This activates muscle spindle sensory fibers, which send a barrage of cord. There, the signals activate the
impulses to the spinal cord, activating motor neurons and triggering muscle contraction. alpha motor neurons that cause the
Flexion withdrawal, shown on the bottom of this image, occurs when you step on a sharp stretched extensor muscle to contract,
object, and your leg is immediately lifted (flexion) from the source of potential injury.
The opposite leg responds with increased extension so that you can maintain your balance, triggering the reflex. Of course, for
called the crossed extension reflex. the leg to kick forward, the antagonist

Movement 3
flexor muscle has to relax at the same injury. When you’re seated in a doc- opposite leg must be activated. With-
time. In fact, the same sensory stim- tor’s office, the “knee jerk” reflex sim- out this additional reaction, called the
ulus that directly activates the motor ply makes your lower leg swing briefly flexion crossed extension reflex, you
neurons controlling the extensor also forward. However, if you were to would lose your balance and fall over
indirectly inhibits the motor neurons jump off a chair (or perform an even after stepping on a tack.
controlling the antagonist flexor. This more dramatic gymnastic dismount) As all these movements occur, the
reciprocal inhibition is accomplished this same reflex would promote the muscles involved provide feedback
by connecting neurons that lie com- contraction of the strong muscles that to the brain with information about
pletely within the spinal cord. When straighten your knees, helping you to where the various body parts are in
these so-called inhibitory interneu- “stick your landing” and remain up- space and how fast they are moving.
rons are activated by the original sen- right. Another protective reflex is the The muscle spindles mentioned earli-
sory stimulus, they send impulses that flexion withdrawal reflex that occurs er supply information about changes
inhibit the motor neurons supplying when your bare foot encounters a in muscle length or stretch. The
the flexor. sharp object. In this case, pain recep- brain, in turn, adjusts the sensitivity
Thus, even the simplest of reflexes tors in the skin send a message to the of the system via a separate set of mo-
involves the synchronous activation spinal cord, alpha motor neurons are tor neurons, gamma motor neurons,
(and inactivation) of multiple sets of activated, and the leg is immediately which keep the muscle spindles taut.
motor neurons controlling both ago- lifted (flexion). At the same time, Other specialized receptors called
nist and antagonist muscles. because your body weight is support- Golgi tendon organs — located where
Many reflexes protect you from ed on both legs, the extensors of the the muscle fibers connect to the
Wright, et al. The Journal of Neuroscience, 2009.

Fallini, et al. The Journal of Neuroscience, 2016.
Specialized cells called motor neurons carry Neurons communicate with muscles at sites called neuromuscular junctions. This image
instructions from the brain along long axons shows a neuromuscular junction in a mouse, with a motor neuron labeled in green and
that stretch from your spinal cord to the neurotransmitter receptors on muscle cells labeled in red.
muscles in your hands and feet. These cells
can be the longest in your body, stretching
the length of your leg to control the
muscles in your feet.

3 Movement
tendon — detect how much force or occur in walking, flying, swimming, ment of functionally related muscles
tension is applied to a muscle during or breathing. Central pattern genera- in an individual body part, such as
ongoing movement, increasing the tors which evolved in primitive verte- your hand or arm; such neurons are
movement’s precision. These feedback brates, are being studied to determine important for finely tuned motor
systems are not unique to reflexes, the degree to which spinal circuitry skills. Other neurons in the motor
but allow the brain to fine-tune how can be co-opted to recover basic cortex can direct the coordinated
working muscles behave during a postural and locomotor function after movement of a limb to a particular
variety of movement tasks — from severe paralysis. point in space — raising your arm
in a defensive position or bringing a
hand to your mouth to deliver a tasty
morsel of food.
Regions that Modulate
The most complex movements that Voluntary Movement

The motor cortex does not
act alone in controlling
you perform, including those requiring complex or skilled voluntary move-
conscious planning, involve input ments. Several other brain regions
participate in parallel circuits or
from the brain. “loops” to modulate motor control.
These regions — including the basal
ganglia, thalamus, cerebellum, and a
large number of neuron groups
located within the midbrain and
those that require a mastery of del- The most complex movements brainstem — also influence the
icate positioning and coordination, that you perform, including those activity of motor neurons in the
such as sipping from a dangerously requiring conscious planning, involve spinal cord. The basal ganglia them-
full teacup, to those that involve a input from the brain. These higher selves encompass two separate path-
targeted application of strength and brain regions initiate voluntary mo- ways. One appears to facilitate the
speed, such as throwing a runner out tion, coordinate complex sequences of desired motor program while the
at first base. movement, and tailor behavioral out- other suppresses unwanted, compet-
put to suit a given situation. Successful ing actions. Along with the thalamus,
VOLUNTARY AND execution of these programs requires the basal ganglia share widespread
COMPLEX MOVEMENTS your brain to relay commands to the connections with motor and sensory
Spinal circuits also play a critical appropriate spinal circuits. areas of the cerebral cortex, allowing
role in controlling more sophisti- Through careful animal experi- these structures to monitor and adjust
cated, voluntary behaviors, such as ments, scientists are just beginning motor performance.
the alternating action of the legs to understand the coordinated series Dysfunction of the basal gan-
during walking. In fact, the rhythmic of interactions that take place among glia can lead to serious movement
patterns of muscle activation that different brain regions during vol- disorders. People with Parkinson’s
produce locomotion — not only in untary movement. One brain area disease experience degeneration of
four-footed animals, but in humans essential for voluntary movement neurons in a brain region called the
— are generated by neurons within is the motor cortex. Neurons in the substantia nigra; these neurons relay
spinal cord and brainstem circuits. motor cortex send signals that directly signals to the basal ganglia using the
When these neuronal circuits (central control the activation of alpha motor neurotransmitter dopamine, a key
pattern generators) are activated, they neurons in the spine. Some of these chemical involved in motor con-
produce the rhythmic patterns that cortical neurons control the move- trol. Depletion of dopamine gives

Movement 3
from controlling limb movements to

eye movement to grip force.
Disturbance of cerebellar function
leads to poor coordination, disor-
Thomas Deerinck, National Center for Microscopy and Imaging Research, University of California, San Diego.
ders of balance, and even difficulties
in speech, one of the most intricate
forms of movement control. Long-
term alcohol abuse is a common cause
of acquired cerebellar degeneration.
Typical symptoms are poor coordina-
tion, an unsteady walk or stumbling
gait, changes in speech, and difficulty
with fine motor skills including eating,
writing, and dressing.
The cerebellum also allows you
to adapt to the unexpected, adjust-
ing your movements so that you can
smoothly lift a box that you expected
to be much heavier, for example.
And, it plays a major role in motor
learning. As you learned to walk or
The cerebellum, shown in this image of a mouse brain, is a region at the back of the brain
speak or practiced a musical instru-
associated with movement. ment or a new dance routine, the
cerebellum refined and sharpened the
rise to the hallmark symptoms of coordinating and fine-tuning skilled motor programs that allow you to
Parkinson’s: tremor, rigidity, and in movement is the cerebellum. The perform these tasks with increasing
some cases, akinesia, an inability to cerebellum receives direct input from accuracy and skill.
move. In contrast, individuals with sensory receptors in the limbs and Considerable evidence also
Huntington’s disease often display head, as well as most areas of the cere- indicates that the cerebellum helps us
uncontrolled jerking or twitching bral cortex. Neurons in the cerebellum recalibrate our movements as our
movements, particularly in the face apparently integrate this sensory in- own bodies change, as we grow taller,
and extremities. These symptoms formation ensuring the proper timing gain or lose weight or muscle mass,
stem from a selective loss of inhibito- and integration of muscle action. This or cope with disease or disability. In
ry neurons in the basal ganglia, which enables us to produce fluid move- that way, the cerebellum facilitates
eliminates the suppression of random ments more or less automatically. The skillful movement through an
involuntary movements. cerebellum is essential to a wide range ever-changing world as we grow up
Another brain region crucial for of motor learning and coordination, and we grow old.

CHAPTER
4
Learning, A
patient known for most of five
decades only by his initials,
H.M., led to one of the most
significant turning points in 20th cen-
Memory & tury brain science: the understanding

that complex functions such as learning
and memory are tied to distinct biolog-
Emotions
ical processes and regions of the brain.
Following a childhood blow to
the head, Henry Molaison developed
severe seizures. Eighteen years later,
still experiencing debilitating symp-
toms, he underwent an experimental
procedure that removed sections of
his medial temporal lobes — includ-
ing most of his two hippocampi. The
seizures abated, but Molaison was left
with permanent amnesia. He could
remember scenes from his childhood,
some facts about his parents, and his-
torical events that occurred before his
surgery, but was unable to form new
conscious memories.
For example, if Molaison met
someone who then left the room,
within minutes he had no recollection
of the person or their meeting. He
experienced every aspect of his daily
life — eating a meal, taking a walk —
as a first. Yet his intellect, personality,
and perception were intact, and he
was able to acquire new motor skills.
Over time, he became more proficient
at tasks such as tracing patterns while
watching his hand movements in a
mirror, despite the fact that he could
never recall performing the task before.
Studied by neuroscientists for 50
years, until his death in 2008 at age
82, Molaison’s intact abilities as well
as his impairments provided evidence
for the roles of the hippocampus and
parahippocampal region in converting
memories from short-term to long-
term, paving the way for further ex-
ploration of brain networks encoding
conscious and unconscious memories.

Learning, Memory & Emotions 4
LEARNING AND MEMORY

Our understanding of how
humans learn and remember is
far from complete, but researchers are
uncovering intriguing new details
about the mechanisms, limits, and
architecture of memory formation.
Thanks in part to H.M., scientists
now know that the medial temporal
lobe, which includes the hippocampus
and parahippocampal regions, works
with other regions of the cerebral
cortex, the brain’s outermost layer, to
form, organize, consolidate, and retrieve
memories. The four major lobes of the
cerebral cortex — frontal, parietal, tem-
poral, and occipital — process sensory
information such as smell, taste, sight,
and sound. Associative regions in the
cortex integrate these sensory inputs,
enabling us to understand our environ- There are several different kinds of memory, and they are processed by different areas of the
brain. The hippocampus, parahippocampal region, and areas of the cerebral cortex work in
ment and encode memories.
tandem to produce memories of facts and events. Other kinds of memories, such as emotion-
al or behavioral memories, are handled by other parts of the brain, including the amygdala,
Declarative Memory striatum, and cerebellum.
Declarative memory is memory for
facts, data, and events. Such conscious
(explicit) memories are called declarative
memories because you can consciously
recall and describe the information.
Declarative memories can be semantic
or episodic. Semantic memories consist
of the cultural knowledge, ideas, and
concepts you’ve accumulated about the
world — for example, names of state
Noguchi, et al. The Journal of Neuroscience, 2016.
capitals, word definitions, how to add

and subtract, or dates of historical events
and their meaning. This type of memory
involves cortical regions well beyond the
hippocampus. Episodic memories are
unique representations of your person-
al experiences. For example, mentally
recalling the sights, sounds, time, space,
and emotions associated with an experi- The dentate gyrus, a portion of the hippocampus responsible for memories of events, is one
ence involves episodic memory. of the few areas of the adult brain where neurogenesis takes place. This image of a mouse
Interestingly, the emotional signif- dentate gyrus shows newborn cells, labeled in blue, along with the support cells called glia,
labeled in red, that will help them migrate to their final destinations. Some of these new cells
icance attached to memories of events will mature to become different types of neurons in the dentate gyrus, where they will play
and experiences is mediated by the important roles in learning and memory.

4 Learning, Memory & Emotions
amygdala. A paired structure consist- no longer be retrieved. gating a maze display specific sequences
ing of two almond-shaped regions Some aspects of working mem- of neuronal activity devoted to right
(amygdala comes from the Greek word ory are coordinated by the prefrontal or left turns. These patterns become
for almond), the amygdala modulates cortex (PFC), the “brain’s executive,” increasingly distinct as the animals learn
“fight-or-flight” responses linked to which also controls attention, deci- the maze. Studies have even shown that
survival. The parahippocampal region sion-making, and long-term planning. learning complex navigational routes
also aids the hippocampus in encoding Specific areas of the PFC monitor causes changes in the hippocampus.
the “what” of episodic memories, rath- information from long-term memory “Grid cells,” don’t represent
er than the “where” or “when.” as well as coordinating working mem- particular locations. Located in the
The type of memory described so ory from multiple brain regions. Brain entorhinal cortex, an area near the
far is the long-term form of declarative imaging studies demonstrate the PFC hippocampus, they represent coor-
dinates that allow the brain to track
your position in space when land-
marks or external cues are absent.
Nondeclarative Memory
The brain seems to have unlimited Nondeclarative memory — also

known as implicit or procedural mem-
ory — is stored and retrieved without
capacity for long-term memories, but conscious effort. You use this type of
short-term memories are limited to memory when you perform learned
motor skills like speaking or riding a
small sums of data for a limited time. bike. H.M. did not lose this type of
memory, as evident in his ability to ac-
quire new motor skills, even though he
couldn’t remember doing them before.
The fact that H.M. (and other
memory. Such memories are stored is particularly active when people con- people with amnesia) show deficits in
throughout a broad network of cortical centrate on keeping something like a some types of memory but not others
areas. H.M. was able to retrieve his phone number in mind. Animal stud- indicates that different types of memo-
previous long-term memories, but not ies suggest that neurons in the PFC fire ries are encoded in separate, but inter-
able to form new ones. in spurts, keeping information active acting, regions of the brain. Motor skill
In contrast, working memory is a or “online” in working memory. H.M. learning, for example, involves many
temporary type of declarative memory, did not lose this type of memory. areas of the brain, but three are espe-
a form of short-term memory that lets Spatial memory is another facet of cially important: the basal ganglia —
you hold a phone number, a sum, a vi- declarative memory. This was identified the “habit center” of the brain — the
sual image, or other data point needed in studies showing that discrete areas, prefrontal cortex, and the cerebellum,
in the present and immediate future. and even individual neurons within an area at the back of the brain involved
While the brain seems to possess un- the brain, are dedicated to processing in motor control and coordination.
limited capacity for long-term memo- specific types of information. For exam-
ries, short-term memories are limited ple, navigational memories involved in Storing Memories in
to relatively small amounts of data creating mental maps are tied to specific Your Synapses
for a limited amount of time. These types of neurons. So-called “place cells” Your brain is able to
data are accessible while they’re being in the hippocampus light up as you form memories and
processed and manipulated but, unless move through a familiar house or room, rewire itself in response to experience
transferred to long-term memory, they or as a rat navigates a known maze. because circuits in your brain change
decay after only a few seconds and can Studies have also shown that mice navi- at synapses — the tiny gaps across

which neurons communicate via receptors — and a molecule called of calcium activate different enzymes:
chemical and electrical signals. The cAMP-response element binding protein kinase proteins in the case of LTP, or
ability of synapses to remodel them- (CREB) are especially important in the phosphatases for LTD. These enzymes
selves is called synaptic plasticity. formation of long-term memories. modify the synapse, making it more or
Encoding a new long-term memory Two opposing but equal pro- less efficient at relaying nerve impulses.
involves persistent changes in the cesses are key for synaptic plasticity: In LTP, a series of molecular events
number and shape of synapses, as long-term potentiation (LTP) and stabilizes the synaptic changes: The in-
well as the amount of neurotransmit- long-term depression (LTD). LTP crease in calcium ions within the post-
ter released and the number of recep- is a long-lasting increase in synaptic synaptic cell activates cyclic adenosine
tors on the postsynaptic membrane. strength, which occurs in many brain monophosphate (cAMP) molecules.
In transmitting information from regions but especially in the hippo- This, in turn, activates several kinds of
one neuron to another, a presynaptic campus. LTD, conversely, decreases enzymes, some of which increase the
(sending) neuron transforms an electri- a synapse’s effectiveness. Experience number of synaptic receptors, making
cal signal into the release of chemical physically changes our brains through the synapse more sensitive to neu-
messengers called neurotransmitters LTP, shown in numerous animal and rotransmitters. In addition, continued
that diffuse across the synaptic gap to human studies to be essential for long- stimulation through repetitive expe-
the postsynaptic (receiving) neuron. term memory consolidation. rience activates CREB. CREB acts in
The membrane of the postsynap- While LTP has been identified the nucleus of the neuron to switch
tic neuron contains proteins called throughout the brain, it has been stud- on a series of genes, many of which
receptors that interact with neurotrans- ied extensively in the hippocampus, the direct protein synthesis. Among the
mitters. Upon binding the neurotrans- brain region associated with encoding many proteins produced are neurotro-
mitters, the receptors unleash a cascade new memories. The precise mechanism phins, which stimulate the growth of
of molecular events that convert the of LTP varies depending on the type the synapse and structural elements,
message back into an electrical sig- of neurons, but, in general, it involves stabilizing increased sensitivity
nal. The receptors then release the an increase in the number of glutamate to neurotransmitters.
neurotransmitters, which are recycled receptors on the postsynaptic neu- The preceding molecular cascade
back into the presynaptic terminal or ron. Glutamate is the most prevalent is essential for memories to become
broken down enzymatically, allowing neurotransmitter in the mammalian long-term. The prevailing view is that
postsynaptic receptors to receive new nervous system, and it binds to declarative memories are encoded in
signals from the presynaptic neuron. several different kinds of receptors. the hippocampus, then transferred to
Scientists have learned a great deal The NMDA and AMPA (α-amino-3- the frontal lobes for long-term storage
about the ways presynaptic and post- hydroxy-5-methyl-4-isoxazolepropionic and consolidation. Research suggests
synaptic neurons remodel themselves. acid) classes of glutamate receptors are that, over time, the hippocampus
The sea slug, Aplysia californica, was an ion channels. Upon binding gluta- becomes less important for retrieving
important animal model for the first mate, they permit calcium and sodium older memories as the frontal cortex
neuroscientists studying synaptic plastici- ions, respectively, to flow into the cell. assumes that task.
ty because its nerve cells are relatively few Increasing the number of receptors As researchers gain new insights
and easy to observe. Researchers iden- on the postsynaptic cell strengthens a into the molecular mechanisms un-
tified chemical and structural changes synapse by allowing the entry of more derlying memory, pharmaceutical and
in relevant nerve cells of Aplysia that electrically conductive ions. technological advances may enable arti-
correlated with simple forms of learning Calcium ions also function as sec- ficial manipulation of synaptic plastici-
and memory. Studies in genetically mod- ond messengers — signaling molecules ty. New treatments could be developed
ified mice have revealed that alterations that set off a chain of molecular events for synapse-related neurological disor-
in gene expression facilitate long-term within cells. LTP boosts the concentra- ders — such as eradication of harmful
changes in synaptic structure. Genes tion of calcium ions inside a postsynap- memories tied to post-traumatic stress
governing a type of glutamate receptor tic cell, while LTD increases it to a lesser disorder (PTSD) — or for boosting
— N-methyl-d-aspartate (NMDA) degree. The differing concentrations our ability to learn and remember.

Ross, et al. The Journal of Neuroscience, 2009.
4 Learning, Memory & Emotions
Oxytocin is a brain chemical closely associated with love. In order to study something as unique as love, researchers look at the brains of
prairie voles, which mate for life. In this image, oxytocin receptors are labeled in light blue, red, and yellow. When researchers increased
oxytocin receptor levels in the brain (right column), they found female voles formed partner preferences faster.
EMOTIONS Anatomy of Emotion attain them. One very familiar type of

In emotional memory, The brain structures most closely learning is dependent on the amyg-
considered another type of linked with emotions are the amygdala: classical conditioning, which
nondeclarative memory, learned dala, the insula or insular cortex, associates a stimulus with reward
emotional responses become attached and the periaqueductal gray, located or punishment.
to stimuli over time after repeated in the midbrain. Neurons from the Through the insula, you expe-
exposure. In the 1970s, anthropologist prefrontal cortex, the amygdala, rience disgust — a strong negative
Paul Ekman identified what he called and the insular cortex project to the reaction to an unpleasant odor, for
the six basic emotions: anger, fear, periaqueductal gray, which in turn instance — that might protect you
surprise, disgust, joy, and sadness. has reciprocal connections with the from ingesting poison or spoiled food.
While scientists have since disputed central nucleus of the amygdala and The insula has also been implicated
the exact number and attributes projections to the thalamus, hypothal- in feeling and anticipating pain, al-
of human emotions, whether emotions amus, brainstem, and deep layers of though its exact function in this arena
are consistent across cultures, the spinal cord. is not well understood. The insula is
or even how to define an emotion, The amygdala integrates emo- believed to take in system-wide inputs
their research has linked some tions, emotional behavior, and and generate subjective feelings about
neural circuits to physiological re- motivation. It interprets fear, helps them; thus linking feelings, internal
sponses that help us survive, interact, distinguish friends from foes, and physiological states, social emotions,
set goals, and initiate actions. identifies social rewards and how to and conscious actions.

The periaqueductal gray, located Motivation: Dopamine and all remains the same.
in a region where incoming sensory and Reward Pathways Interestingly, recent research
information is acted on by higher Although relatively few neurons shows that dopaminergic responses
brain centers, has been tied to pain in the mammalian central nervous vary among people. Some people’s
perception as well as stress responses system generate the neurotransmitter brains respond more strongly to re-
including defensive and reproductive dopamine, these dopaminergic neu- wards than punishments, while others
behaviors, maternal attachment, and rons influence multiple brain func- respond more strongly to punish-
anxiety. Receptors for pain-reducing tions including voluntary movement ments. The amygdala has been im-
compounds such as morphine and and a variety of behavioral processes plicated in various aspects of reward
oxycodone are clustered in the such as mood, reward, addiction, learning and motivation. Researchers
periaqueductal gray. stress and memory. at Vanderbilt University found that
When something is very rewarding, “go-getters” who are more willing to
Motivation: Affective we are more likely to remember it. That work hard have greater dopamine sig-
Decision-Making is because dopamine influences the syn- naling in the striatum and prefrontal
Human actions are driven by apses in the entire reward pathway — cortex — two areas known to impact
necessities — food, sleep, sex, avoid- the hippocampus, amydgala, and the motivation and reward.
ance of pain — and by rewards, but prefrontal cortex — to create emotional While the brain’s reward system
our responses and actions are not associations with rewards. And the me- typically reinforces behaviors associat-
always logical. While little is known solimbic pathway, sometimes called the ed with rewards and prevents behav-
about exactly how the brain transforms “reward pathway,” is a major pathway iors leading to punishment, aberrant
feelings into decisions, researchers have for dopamine, connecting the mid- circuitry can lead to inappropriate
developed theoretical models about brain’s ventral tegmental area (VTA) to aggression, a symptom of some neu-
decision-making. Affective decision- the nucleus accumbens. It is involved ropsychiatric disorders. For example,
making involves choices under risky in cognitive processing of rewards and the lateral habenula, a major node in
and uncertain conditions. An active motivation. Neurons that release dopa- the reward circuitry, appears to en-
area of neuroscience research is inves- mine are activated in response to signals code punishment by inhibiting dopa-
tigating how the brain balances reward that a reward will be given. mine release, and dysfunction of the
and risk, and how emotional state Surprisingly, it’s not the reward lateral habenula has been linked to
affects this balance. itself, but the expectation of a reward disorders involving inappropriate ag-
Emotionally centered decision- that most powerfully influences the gression. The amygdala has also been
making changes with age — possibly emotional reaction. Reward learning associated with negative emotions.
because the lateral prefrontal cortex, occurs in response to something un- Stimulating some areas can trigger
responsible for self-regulation, ma- expected — when the actual reward rage and aggression, while removing
tures gradually in adolescents. Teens’ differs from what was predicted. If specific sections of the amygdala will
developing brains and high sensitivity a reward is greater than anticipated, make lab animals more docile. Recent
to peer acceptance might be related to dopamine signaling increases. If a studies in lab animals have also sug-
their increased tolerance for risky be- reward is less than expected, dopa- gested that aggression can result from
haviors. Older adults might also make mine signaling decreases. In contrast, inappropriate activation of the brain’s
more risky decisions, as PFC function a correctly predicted reward does not reward systems in response to violent
diminishes with age. elicit changes in dopamine signaling, social stimuli.

CHAPTER
5
Thinking, F
rom the moment you wake up,
your brain is bombarded by
stimuli: the sound of birds sing-
ing or the rumble of trucks, the smell
Planning & of coffee, the brightness and warmth

of sunlight streaming through your
window. Fortunately, your brain is adept
Language
at filtering this flood of information and
making a decision about what actions to
take. Is it a workday or a weekend? What
would taste good for breakfast? How
warm a sweater do you need? Every mo-
ment you’re conscious, you are thinking,
planning, and making decisions.
But how do you think? What is
happening in our brains when we re-
flect on last night’s party or puzzle over
what to wear today? Can other animals
think the way that humans do? In
order to think, your brain has to
make sense of the noisy, chaotic world
around you. The first filter for that
information is your perception, which
arises from the senses whose processing
we considered in Chapter 2. The next
step is interpreting those perceptions,
which your brain does by comparing
them to memories of past experiences
and observations.
Constructing Representations
Because your brain’s capacity to
store this information in short-term
memory is limited, it builds fairly sim-
ple representations of people, places,
objects, and events as references. To
really make sense of our moment-to-
moment perceptions, the brain relies
on its complex network of associations
assembled from prior experience. These
connections enable your brain to deal
with variable perceptions. For example,
you can identify a dog even if it is a
different breed or color than any you
have seen before. A bicycle still registers
as a bicycle, even if it is obscured so
that only one wheel is visible.
Thinking, Planning & Language 5
Constructing these representations pitcher, garbage can, and roll of paper as complex skills and representations
relies on semantic memory, a form of towels — saying “This is a sink … are built up by integrating information
declarative knowledge that includes Oh! This one could be a sink … This from simpler inputs. One example of
general facts and data. Scientists are just is also a sink,” before finally finding this organization is the way the brain
beginning to understand the nature and the real sink and filling the cup. But represents words. Regions that encode
organization of cortical areas involved in striking contrast, he could easily words include the posterior parietal
in semantic memory, but it appears that identify objects when he closed his cortex, parts of the temporal lobe, and
specific cortical networks are specialized eyes and felt them; he could also name regions in the prefrontal cortex (PFC).
for processing certain types of infor- things that he heard, such as a rooster’s Together, these areas form the seman-
mation. Studies using functional brain “cock-a-doodle-doo.” tic system, a constellation that re-
imaging have revealed regions of the Researchers concluded that sponds more strongly to words than to
cortex that selectively process different D.B.O.’s strokes had damaged his other sounds, and even more strongly
categories of information such as ani- brain in ways that prevented visual to natural speech than to artificially
mals, faces, tools, or words. input from being conveyed to anterior garbled speech. The semantic system
Recordings of the electrical temporal regions where semantic pro- occupies a significant portion of the
activity of individual brain cells show cessing occurs. This blocked his access human brain, especially compared
that specific, single cells may fire when to the names of objects that he could to the brains of other primates. This
someone looks at photographs of a see, but not his ability to name objects difference might help explain humans’
particular person, but remain quiet he could touch. unique ability to use language.
when viewing photographs of other Separate areas within this system
people, animals, or objects. So-called Regional Specialization encode representations of concrete or
“concept cells” work together in assem- and Organization abstract concepts, action verbs, or so-
blies. For example, the cells encoding Experts have learned from people cial information. Words related to each
the concepts of needle, thread, sewing, like D.B.O. that damage to certain other, such as “month” and “week,”
and button may be interconnected. areas of the temporal lobes leads to tend to activate the same areas, where-
Such cells, and their connections, form problems with recognizing and iden- as unrelated words, such as “month”
the basis of our semantic memory. tifying visual stimuli. This condition, and “tall,” are processed in separate
Concept cells reside in the tem- called agnosia, occurs in several forms, areas of the brain. Many studies using
poral lobe, a brain area that specializes depending on the exact location of the a technique called functional magnetic
in object recognition. Scientists made brain damage. resonance imaging (fMRI) to measure
great strides in understanding memory One such region is the fusiform brain activity in response to words
by studying H.M., a man with severe face area (FFA). Located on the un- have found more extensive activation
amnesia, who was discussed in Chap- derside of the temporal lobe, the FFA in the left hemisphere, compared to
ter 4. Similarly, our understanding is critical for recognizing faces. This the right hemisphere. However, when
of thinking and language has been distinct area responds more strongly to words are presented in a narrative or
informed by studying people with images with than without faces, and other context, they elicit fMRI activity
unique deficits caused by particular bilateral damage to this area results on both sides of the brain.
patterns of brain damage. in prosopagnosia or “face blindness.” Written language involves addi-
Consider the case of D.B.O., a Similarly, a nearby region called the tional brain areas. The visual word
72-year old man who suffered multiple parahippocampal place area responds form area (VWFA) in the fusiform
strokes. In tests run by researchers, to specific locations, such as pictures of gyrus recognizes written letters and
D.B.O. could identify only 1 out of buildings or particular scenes. Other words — a finding that is remarkably
20 different common objects by sight. areas are activated only by viewing consistent across speakers of different
He also struggled when he was asked certain inanimate objects, body parts, languages. Studies of the VWFA reveal
to take a cup and fill it with water or sequences of letters. connections between it and the brain
from the sink. He approached several Within these brain areas, infor- areas that process visual informa-
different objects — a microwave, water mation is organized into hierarchies, tion, bridges that help the brain link

5 Thinking, Planning & Language
meaning to written language. Like-

wise, there are specific brain areas that
represent numbers and their meaning.
These concepts are represented in the
parietal cortex with input from the
occipitotemporal cortex, a region that
participates in visual recognition and
reading. These regions work together
to identify the shape of a written
number or symbol and connect it to
its concept, which can be broad: For
example, the number “3” is applied
to sets of objects, the concept of trios,
and the rhythm of a waltz.
James.mcd.nz.
Thus, through constructing

hierarchical, connected representations
of concepts, the brain is able to build
meaning. All of these skills depend Language is a complex cognitive ability, involving several areas of the brain. The blue area in
this image is Broca’s area, which is vital for speech production. The green area is Wernicke’s
on the fluid and efficient retrieval and area, which is responsible for understanding others’ speech. They and other areas work in
manipulation of semantic knowledge. tandem for many types of communication.
LANGUAGE PROCESSING lesion was located is still called Broca’s answers to questions, used made-up
In mid-19th century France, area, and it is vital for speech produc- words, and had difficulty naming fa-
a young man named Louis tion. Further studies of aphasia have miliar items. After her death, Wernicke
Victor Leborgne came to live at the greatly increased our knowledge about determined that she had damage in her
Bicêtre Hospital in the suburbs south the neural basis of language. left temporal lobe. This caused her dif-
of Paris. Oddly, the only word he Broca’s aphasia is also called ficulty in comprehending speech, but
could speak was a single syllable: “non-fluent” aphasia, because speech not producing it, a deficit that is now
“Tan.” In the last few days of his life, production is impaired but compre- known as “Wernicke’s aphasia,” or “flu-
he met a physician named Pierre Paul hension is mostly intact. Damage ent aphasia.” Fluent aphasic patients
Broca. Conversations with the young to the left frontal lobe can produce might understand short individual
man, whom the world of neuroscience non-fluent aphasias, in which speech words, and their speech can sound nor-
came to know as Patient Tan, led output is slow and halting, requires mal in tone and speed, but it is often
Broca to understand that Leborgne great effort, and often lacks complex riddled with errors in sound and word
could comprehend others’ speech and word or sentence structure. But while selection and tends to be unintelligible.
was responding as best he could, but their speaking is impaired, non-fluent Another type of aphasia is called
“tan” was the only expression he was aphasics still comprehend spoken lan- “pure word deafness,” which is caused
capable of uttering. guage, although their understanding of by damage to the superior temporal
After Leborgne died, Broca per- complex sentences can be poor. lobes in both hemispheres. Patients
formed an autopsy and found a large Shortly after Broca published his with this disorder are unable to com-
damaged area, or lesion, in a portion findings, a German physician, Carl prehend heard speech on any level.
of the frontal lobe. Since then, we Wernicke, wrote about a 59-year-old But they are not deaf. They can hear
have learned that damage to particular woman he referred to as S.A., who had speech, music, and other sounds, and
regions within the left hemisphere lost her ability to understand speech. can detect the tone, emotion, and even
produces specific kinds of language Unlike patient Leborgne, S.A. the gender of a speaker. But they can-
disorders, or aphasias. The portion could speak fluently, but her utteranc- not link the sound of words to their
of the frontal lobe where Leborgne’s es made no sense: she offered absurd meaning. (They can, however, make

perfect sense of written language, be- movements in the sequences required poral lobe is under intense investiga-
cause visual information bypasses the for speech. The disability is also tion as a site that might participate in
damaged auditory comprehension area accompanied by difficulty with spoken sentence-level comprehension. Recent
of the temporal lobe.) and written language. work has also identified a sensory-mo-
Although Broca and Wernicke’s Remarkably, many insights tor circuit for speech in the left poste-
work emphasized the role of the left into human speech have come from rior temporal lobe, which is thought to
hemisphere in speech and language studies of birds, where it is possible to help communication between the sys-
ability, scientists now know that rec- induce genetic mutations and study tems for speech recognition and speech
ognizing speech sounds and individual their effects on singing. Just as human production. This circuit is involved in
words actually involves both the left babies learn language during a special speech development and is likely to
and right temporal lobes. Nonetheless, developmental period, baby birds support verbal short-term memory.
producing complex speech is strongly learn their songs by imitating a vocal
dependent on the left hemisphere, model (a parent or other adult bird) COGNITION AND
including the frontal lobe as well as during an early critical period. Like EXECUTIVE FUNCTION
posterior regions in the temporal lobe. babies’ speech, birds’ song-learning Executive Function
These areas are critical for accessing also depends on auditory feedback Some of the most complex
appropriate words and speech sounds. — their ability to hear their own processes in the brain occur in
Reading and writing require attempts at imitation. Interestingly, the prefrontal cortex (PFC), the outer,
the involvement of additional brain studies have also revealed that FOXP2 folded layers of the brain located just
regions — those controlling vision and mutations can disrupt song develop- behind your forehead. The PFC is one
movement. Earlier, we mentioned that ment in young birds, much as they do of the last regions of the brain to
sensory processing of written words in humans. develop, not reaching full maturity
entails connections between the brain’s Imaging studies have revealed that until adulthood. This is one reason
language areas and the areas that pro- disruption of FOXP2 can severely why children’s brains function quite
cess visual perceptions. In the case of affect signaling in the dorsal striatum, differently from those of adults. The
reading and writing, many of the same part of the basal ganglia located deep processing that takes place in this area
centers involved in speech comprehen- in the brain. Specialized neurons in the is known as executive function. Like
sion and production are still essential, dorsal striatum express high levels of the chief executive officer (CEO) of a
but require input from visual areas that the product of FOXP2. Mutations in company, the PFC supervises every-
analyze the shapes of letters and words, FOXP2 interrupt the flow of informa- thing else the brain does, taking in
as well as output to the motor areas tion through the striatum and result sensory and emotional information
that control the hand. in speech deficits. These findings show and using this information to plan and
the gene’s importance in regulating execute decisions and actions.
New Insights in signaling between motor and speech Specific areas of the PFC support
Language Research regions of the brain. Changes in the executive functions such as selecting,
Although our under- nucleotide sequence of FOXP2 might rehearsing, and monitoring informa-
standing of how the have influenced the development tion being retrieved from long-term
brain processes language is far from of spoken language in humans and memory. To serve these functions, the
complete, recent molecular genetic explain why humans speak and chim- PFC also interacts with a large net-
studies of inherited language disorders panzees do not. work of posterior cortical areas that
have provided important new insights. Functional imaging studies have encode specific types of information
One language-associated gene, called also identified brain structures not — for example, visual images, sounds,
FOXP2, codes for a special type of previously known to be involved in words, and the spatial location in
protein that switches other genes on language. For example, portions of which events occurred.
and off in particular parts of the brain. the middle and inferior temporal lobe Although more fully evolved in
Rare mutations in FOXP2 result in participate in accessing the meaning of humans, some aspects of executive
difficulty making mouth and jaw words. In addition, the anterior tem- function are displayed by other

5 Thinking, Planning & Language
requires active rehearsal and conscious
National Institute on Deafness and Other Communication Disorders, National Institutes of Health.
focus to maintain.
The third key component of ex-
ecutive function is shifting, or mental
flexibility, which allows you to adjust
your ongoing behavior when condi-
tions require it. For example, in the
card sorting task, people must figure
out (from the examiner’s simple “yes/
no” responses) that they must switch
from sorting by one rule, such as suit,
and begin sorting by another, such
as number. People with damage to
their PFC have great difficulty doing
this and tend to stick with the first
sorting rule. Children’s ability to shift
Scientists can observe the brain activity underlying advanced cognitive functions, such as successfully between tasks follows a
creativity. In this image, researchers were able to measure activity in the brains of jazz musi-
cians while they improvised. This gave them a clue as to what brain regions are associated
developmental course through adoles-
with creative thinking. cence. It appears that preschool-aged
children can handle shifts between
animals. Studies in nonhuman pri- automatic imitation of adults, is very simple task sets in a card-sorting task
mates have shown that neurons in the hard for three-year-olds, but four- and later handle unexpected shifts be-
PFC keep information active or “in year-olds perform significantly better. tween increasingly complex task sets.
mind” while the animal is carrying As people grow older, they wield this Both behavioral and physiological
out a task that depends on it. This ability ever more skillfully. measures indicate that the ability to
is analogous to working memory In addition to inhibition, this monitor one’s errors is evident during
in humans, which is a form of hand game and similar tasks rely on adolescence; by mid-adolescence,
executive function. working memory, which is the ability more complex task switching reaches
Executive function can be con- to hold a rule in mind while you decide adult-like levels. Because of its greater
sidered a blend of three core skills: how to act (in this case, opposite the need for multiple cognitive process-
inhibition, working memory, and demonstrator). When you have new es, mature shifting likely involves a
shifting. Inhibition is the ability to experiences, information initially enters network of activity in many regions
suppress a behavior or action when it your working memory, a transient form of the PFC.
is inappropriate — such as calling out of declarative or conscious memory. Many of the changes in execu-
loudly when one is in an audience or Working memory depends on both the tive functioning ability are gradual,
classroom. Even toddlers demonstrate PFC and the parietal lobe. It gives you although the changes are more appar-
hints of a developing inhibition ability, the ability to maintain and manipulate ent in young children. The PFC is the
as shown in their ability to delay (for information over a brief period of time main region implicated in executive
at least a short period of time) eating without external aids or cues — such as functioning; however, the skills that
a treat placed in front of them. By the remembering a phone number with- fall under this umbrella use inputs
time children reach preschool, they out writing it down. Most people can from all over the brain. Interestingly,
can tackle more complex inhibition memorize and recite a string of num- the activity level associated with
tasks, such as “Lucia’s hand game,” bers or words over a brief period of executive function actually decreases
in which they are told to make a fist time, but if they are distracted or there as children and adolescents mature,
when shown a finger and a finger is a time lag of many minutes or hours, reflecting the fact that these circuits
when shown a fist. This test, which they are likely to forget. This shows the become more fine-tuned and efficient
requires inhibiting their more duration of working memory, which as the neuron networks mature.

Decision-Making The orbitofrontal cortex, a region drives these processes by scanning

The fundamental skills of exec- of the PFC located just behind the people’s brains with fMRI as subjects
utive function — inhibition, eyes, appears to be important in watch video clips of other people.
working memory, and shifting — pro- affective decision-making, especially in Several regions in the medial
vide the basis for other skills. One of situations involving reward and pun- prefrontal cortex help us make judg-
these is decision-making, which ishment. The area has been implicated ments about ourselves and others.
requires a person to weigh values, in addiction as well as social behavior. In addition, a specific region at the
understand rules, plan for the future, border of temporal and parietal lobes,
and make predictions about the Social Neuroscience the temporoparietal junction (TPJ),
outcomes of choices. Humans, like many other appears to focus on others and not on
You make many different types animals, are highly social the self. The TPJ is also activated when
of decisions every day. Some of these creatures. Accordingly, large parts of we watch others engage in actions that
rely primarily on logical reasoning — our brain are dedicated to processing seem at odds with their intentions or
for example, when you compare the information about other people. Social in actions intended to be deceptive.
timetables for the bus and subway neuroscience refers to the study of A popular, though controversial,
to determine the quickest way to get neural functions that underlie inter- theory of social cognition centered
to a friend’s house. Other decisions personal behavior, such as reading on the discovery of “mirror neurons.”
have emotional consequences at stake, social cues, understanding social rules, In the 1990’s, scientists identified
like when the person you’re trying to choosing socially-appropriate respons- neurons in the motor cortex of rhesus
impress offers you a cigarette — your es, and understanding oneself and macaques that fired when the mon-
desire to be accepted might outweigh others. The latter process is known as keys performed a specific action. They
your rational consideration of smok- “mentalizing” — making sense of your were astonished to find these neurons
ing’s harms. This is an example of own thought processes and those of also fired when the monkeys simply
affective decision-making (Chapter 4). others. The medial PFC, as well as watched another person or monkey
Both types of decision-making some areas of the lateral PFC, are perform that same action. The findings
involve the brain’s prefrontal cortex highly involved in these skills. prompted speculation that mirror neu-
(PFC). In particular, activity in the Mentalizing underlies some of our rons underlie our ability to understand
lateral PFC is especially important most complex and fascinating mental another person’s actions. Additional
in overriding emotional responses in abilities. These include empathy and studies revealed humans also possessed
decision-making. The area’s strong “theory of mind,” which is under- mirror neurons, and in even wider
connections with brain regions related standing the mental states of others brain networks.
to motivation and emotion, such as and the reasons for their actions. Mirror neurons permeated pop-
the amygdala and nucleus accumbens, Until recently, research devoted little ular media. Within a decade of their
seem to exert a sort of top-down emphasis to the social and emotional discovery, however, mirror neurons’
control over emotional and impulsive abilities needed for these higher-order role in social cognition was called into
responses. For example, brain imaging mental functions, but now such topics question — many scientists argued
studies have found the lateral PFC is are being avidly studied. that there was little direct evidence
more active in people declining a small An obvious way that we under- supporting mirror neurons’ purported
monetary reward given immediately stand the mental states of others is by roles in theory of mind, mentalizing,
in favor of receiving a larger reward in observing their actions. This requires and empathy.
the future. This is one of the last areas the brain to see and recognize others’ Researchers are continuing to in-
of the brain to mature — usually in movements and facial expressions, and vestigate mirror neurons, as well as the
a person’s late 20s — which explains then draw inferences about the feelings complexities of the human brain that
why teens have trouble regulating and intentions that drive them. Scien- allow us understand and empathize
emotions and controlling impulses. tists have learned how brain activity with others.

CHAPTER
6
The N
eurons develop through
delicate and carefully cho-
reographed processes that
take place while an embryo grows.
Developing Signaling molecules “turn on” certain

genes and “turn off ” others, initiating
the formation of immature nerve cells.
Brain
During the next stage — cell division,
also called proliferation — the pool of
early-stage brain cells increases by bil-
lions. Finally, during migration, these
newly formed neurons travel to their
final destinations. The nervous system
formed by these processes is active
throughout life, making new connec-
tions and fine-tuning the way messages
are sent and received. In this chapter,
you will learn about the amazing early
development of your ever-changing
nervous system.
THE JOURNEY
OF NERVE CELLS
Formation and Induction
During the very early stages of
embryonic development, three layers
emerge — the ectoderm (outer-most
layer), mesoderm (middle layer),
and endoderm (inner-most layer).
Although the cells in each layer con-
tain identical DNA instructions for
development, these layers ultimately
give rise to the rich variety of tissue
types that make up the human body.
The explanation for this diversity lies
in signals produced by surrounding
tissues. Those signals turn certain
genes on and others off, thus inducing
the development of specific cell types.
Signals from the mesoderm trigger
some ectoderm cells to become nerve
tissue, a process called neural induc-
tion. Subsequent signaling interactions
refine the nerve tissue into the basic
categories of neurons or glia (support
cells), and then into subclasses of each
cell type.

The Developing Brain 6
After three week’s gestation, the human brain begins to form. The first stage is the neural tube, pictured at left. By four weeks, the individual
sections of the brain can be recognized. In 6 months, the ridges of the brain can be observed.
The fate of a developing cell is Proliferation only a few neural stem and progenitor
largely determined by its proximity In the brain, neurons arise cells remain within the brain, and neu-
to various sources of signaling mol- from a fairly small pool of neurogenesis in adulthood is limited to a
ecules. The concentration of each ral stem and progenitor cells, special few regions of the brain, such as those
type of signaling molecule decreases cells that can divide and become a involved with memory.
farther from its source, creating variety of mature cell types. Before Scientists have proposed that
gradients throughout the brain. achieving their mature cell fate, this protein defects causing a premature
For example, a particular signaling pool of cells undergoes a series of switch from symmetric to asymmetric
molecule, called sonic hedgehog, divisions — increasing the number of divisions may be a cause of micro-
is secreted from mesodermal tissue cells that will ultimately form the cephaly. This disorder, characterized
lying beneath the developing spi- brain. Early divisions are symmetric by a severe reduction in brain size, is
nal cord. As a result of exposure to — the split results in two identical associated with serious neurological
this signal, adjacent nerve cells are daughter cells, both able to keep disabilities and sometimes death in
converted into a specialized class dividing. But as these divisions infancy. Similarly, excessive prolifera-
of glia. Cells that are farther away progress, the cells begin to divide tion of brain cells can lead to a disor-
are exposed to lower concentrations asymmetrically, giving rise to only one der called megalencephaly — a brain
of sonic hedgehog, so they become daughter cell that keeps proliferating that is abnormally large and heavy —
motor neurons that control the and a second that progresses towards which is also associated with a variety
movement of muscles. An even lower its ultimate cell fate as a neural or glial of neurodevelopmental complications.
concentration promotes the forma- cell (the exact sequences and ultimate
tion of interneurons, which don’t fates vary by species). Migration
relay messages to muscles but to oth- This proliferative process permits After neural induction and pro-
er neurons. Interestingly, the mech- rapid growth during early development liferation occur, new neurons journey
anism of this molecular signaling is of the brain, with billions of cells being from the inner surface of the embry-
very similar in species as diverse as produced in a matter of weeks. After onic brain, where they formed, to their
flies and humans. that series of divisions is complete, long-term locations in the brain. This

6 The Developing Brain
migrate sideways, or tangentially

(rather than radially), moving parallel
to the brain’s surface and across the
radial cortical columns.
Migration is a finely tuned process
that can be influenced by many fac-
tors. For example, exposure to alcohol,
cocaine, or radiation, can prevent
proper migration, resulting in mis-
placement of cells, which can lead to
intellectual disability or epilepsy. Fur-
thermore, mutations in the genes that
Winkle, et al. The Journal of Neuroscience, 2016

regulate migration have been shown to
cause rare genetic forms of intellectual
disability and epilepsy in humans.
Making Connections
After neurons reach
their final locations,
they begin making the connections
New neurons, shown here in the mouse, are born throughout life in a specific region of the
brain’s hippocampus. This region, known as the dentate gyrus, is involved in pattern
that will determine how particular
separation, the ability to discriminate between very similar memories. functions such as vision or hearing can
occur. Induction, proliferation, and
process is called migration, and it be- tricular zone, which lies along the inner migration occur internally during fetal
gins three to four weeks after a human surface of the tube, toward the border development, but the next phases of
baby is conceived. At this time, the of the marginal zone, or outer surface. brain development depend increasing-
ectoderm starts to thicken and build After neurons stop dividing, they form ly on external experience. After birth,
up along the midline of the embryo. an intermediate zone where they grad- factors such as watching a mobile spin,
As the cells continue to divide, a flat ually accumulate as the brain develops. listening to a voice, and even proper
neural plate grows, followed by the A variety of guidance cue neurons to nutrition influence the connections
formation of parallel ridges, some- migrate to their final destinations. formed by neurons.
what resembling the creases in a paper The most common guidance Neurons become interconnected
airplane, that rise along either side of mechanism, accounting for about through their short branches called
the midline. These ridges extend from 90 percent of migration in humans, dendrites and long axons — two
the “head end”, where the future brain is the radial glia, which project types of processes that extend from
will form, along the length of the em- radially from the intermediate zone a neuron’s cell body (soma). Axons
bryo where the future spinal cord will to the cortex. Neurons use these glia produce and transmit signals to other
develop. Within a few days, the ridges as scaffolding, inching along glial neurons, and dendrites receive signals
fold toward each other and fuse into projections until they reach their final from the axons that contact them.
a hollow neural tube. The head end destinations. This process of radial To reach their targets, axons can span
of the tube thickens into three bulges migration occurs in an “inside-out” distances many times the size of their
that form the hindbrain, the midbrain, manner; that is, the cells that arrive cell body, many crossing to the op-
and the forebrain. Later in the process, the earliest (the oldest ones) form the posite side of the brain. The longest
at week 7 in humans, the first signs of deepest layer of the cortex, whereas human axons are in the periphery,
the eyes and the brain’s hemispheres the late-arriving (youngest) neurons extending from the lower spinal cord
appear. As new neurons are produced, form the outermost layer. Through a all the way to muscles in the toes.
they move from the neural tube’s ven- different mechanism, other neurons Given the distance from spinal cord

The Developing Brain 6
to toes of a basketball player — a Synapse Formation Dendrites are also actively involved in
meter or more — such axons might Once axons reach their targets, initiating contact with axons, and both
be nearly a million times longer than a specialized connection called sides produce proteins that span the
their diameter! a synapse begins to form. At the space between them and anchor the
A developing axon grows by synapse, only a tiny space separates synapse together.
the extension of its growth cone, an the signaling portion of the axon Once initial contact is established,
enlargement at the tip of the axon from the receiving portion of the a synapse continues to differentiate.
that actively explores the environment dendrite. Electrical signals that travel On the presynaptic side, the tiny axon
to seek out its precise destination. A down the axon trigger the release of terminal that contacts the dendrite
growth cone is guided to that final chemical messages called neurotrans- becomes specialized for releasing neu-
destination by molecular cues in its mitters, which diffuse across this rotransmitters, stocking itself with neu-
environment. Some of these molecules
stud the surfaces of cells, while others
are secreted into areas near the growth
cone. Receptors on the growth cone
A human brain contains trillions of

enable its responses to these environ-
mental cues. Binding of environmen-
tal molecules tells the growth cone
whether to move forward, stop, recoil,
or change direction. Attractive cues lay
these synapses, which gives rise
a path growth cones follow, while re-
pellent molecules funnel growth cones
to the brain’s astounding capacity
through precise corridors. Signaling
molecules include families of proteins
for information processing.
with names such as netrin, sema-
phorin, and ephrin.
One truly remarkable finding is
that most of these proteins are com- space and are received by receptors on rotransmitter packets, and proteins that
mon to many organisms — worms, the target dendrite. Such chemical enable those packets to be held in place
insects, and mammals including cues can either promote or hinder the and then released. On the dendritic
humans. Each family of proteins is generation of a new electrical signal — or postsynaptic — side, receptors
smaller in flies or worms than in mice in the receiving neuron. The com- that respond to those neurotransmit-
or people, but its functions are very bined effects of such cues from ters begin to dot the membrane. Both
similar. As a result, simpler animals thousands of synapses ultimately processes ensure that a synapse can
are highly useful experimental models determine how a receiving neuron transmit signals quickly and effectively.
for gaining knowledge that direct- responds. A human brain contains New evidence has implicated a
ly applies to humans. For example, trillions of these synapses, which gives third important player in the proper
netrin was first discovered in a worm, rise to the brain’s astounding capacity formation of a synapse. Astrocytes
where it was found to guide neurons for information processing. are a type of glial cell in the brain
around the worm’s “nerve ring.” Later, For this processing to occur previously thought to simply pro-
vertebrate netrins were found to guide properly, the formation of synaptic vide scaffolding and passive support
axons around the mammalian spinal connections must be highly specific. to neurons. They are now known to
cord. When receptors for netrins were Some specificity is the result of the exert their own influence on synaptic
then discovered in worms, this knowl- mechanisms that guide each axon to development and function. Many
edge proved invaluable in finding the its proper target. Additional mole- synapses in the brain are contacted
corresponding, and related, receptors cules mediate target recognition when by astrocytes, and studies in rodents
in humans. the axon reaches the proper location. have found that a single astrocyte can

6 The Developing Brain
contact thousands of synapses across influenced by factors that come from distinct group of neurons. For exam-
multiple neurons. The importance of the location of the synapse itself. ple, nerve growth factor is important
astrocytes in synapse formation is also for the survival of sensory neurons. It
shown in other studies. Some neu- Myelination has recently become clear that apopto-
rons form only a few synapses when Insulation that covers wires sis is maintained into adulthood but
developing in a culture dish from preserves the strength of electrical constantly held in check. Based on
which astrocytes are absent, and recent signals that travel through them. The this, researchers have found that
research has discovered that molecules myelin sheath that covers axons serves injuries and some neurodegenerative
secreted by astrocytes regulate aspects a similar function. Myelination, the diseases kill neurons not by directly
of synaptic development. fatty wrapping of axons by extensions inflicting damage but by activating the
Scientists are learning that mol- of glia, increases — by as much as 100 cells’ own death programs. This
ecules from multiple sources work times — the speed at which signals can discovery — and its implication that
together to promote proper synapse travel along axons. This increase is a death need not follow insult — have
formation. It is now thought that function of how the sheath is wrapped, led to new avenues for therapy.
defects in such molecules could con- with somewhat regularly spaced gaps Just as too many brain cells
tribute to disorders such as autism. In called nodes of Ranvier interrupting develop early on, these cells initially
addition, the loss of certain other mol- the sheath. The alternating pattern of form an excessive number of connec-
ecules might underlie the degradation insulation and nodes allows electrical tions. In primates, for example, neural
of synapses that occurs during aging. signals to move down an axon faster, projections from the two eyes to the
An array of signals determines jumping from one node to the next. brain initially overlap; then, in some
which type of neurotransmitter a neu- This phenomenon, called saltatory con- portions of the brain, they sort into
ron will use to communicate. For some duction (“saltatory” means “leaping”), is separate territories devoted to one eye
cells, such as motor neurons, the type responsible for more rapid transmission or the other. Furthermore, connections
of neurotransmitter is fixed (acetylcho- of electrical signals. Formation of my- between neurons in a young primate’s
line), but for other neurons, it is not. elin occurs throughout the lifespan. cerebral cortex are more numerous and
Scientists have found that when cer- twice as concentrated as in an adult
tain immature neurons are maintained Paring Back primate. The pruning of these excess
in a culture dish with no other cell After its initial growth, the connections is heavily dependent on
types, they produce the neurotransmit- neural network is pared back, the relative activity of each connec-
ter norepinephrine. In contrast, when creating a more efficient system. In tion. Connections that are active and
the same neurons are cultured with fact, only about half the neurons generating electrical currents survive,
specific cells, such as cardiac tissue, generated during development survive while those with relatively little activity
they produce the neurotransmitter to function in an adult. Entire popula- are lost. Astrocytes and other glia also
acetylcholine. Just as genetic and tions of neurons are removed through play an important role in this process.
environmental signals can modulate apoptosis, a process of programmed For example, astrocytes are known to
the development of specialized cells, cell death initiated in the cells. Apop- aid the formation of eye-specific con-
a similar process leads to production tosis is activated if a neuron fails to nections by engulfing and eliminating
of specific neurotransmitters. Many receive enough life-sustaining chemical unnecessary synapses. Thus, at least to
researchers believe that the signal to signals called trophic factors, which are some extent, the circuits of the adult
engage the gene, and therefore the produced in limited quantities by brain are formed by pruning away
final determination of the chemical target tissues. Each type of trophic incorrect connections to leave only
messenger a neuron will produce, is factor supports the survival of a the correct ones.

CHAPTER
7
Infant, T
he amazing capabilities of
the human brain arise from
astoundingly intricate com-
munication among billions of interact-
Child & ing cells. Understanding the processes

by which brain cells form, become
specialized, travel to their appropri-
Adolescent
ate locations, and connect with each
other in increasingly elaborate adaptive
networks is the central challenge of
developmental neurobiology.
Brain Advances in the study of brain

development have become increasingly
relevant for medical treatments. For
example, several diseases that scientists
once thought were purely adult disor-
ders are now being considered from
a developmental perspective. Schizo-
phrenia might actually occur because
pathways in the brain and connections
to it formed incorrectly in early life.
Other research suggests that genes that
influence brain development could
also play a role in a person’s suscepti-
bility to autism spectrum disorders.
And regeneration following brain inju-
ry is now considered a realistic possi-
bility, thanks to expanding knowledge
of how neurons form connections
during early development.
Knowing how the brain was first
constructed is an essential step toward
understanding its later ability to reor-
ganize in response to external influ-
ences or injuries. As the brain develops
from the embryo to the adult, unique
attributes evolve during infancy and
childhood that will influence people’s
differences in learning ability as well as
their vulnerability to specific brain dis-
orders. Neuroscientists are starting to
discover general principles that underlie
these intricate developmental processes.
THE FIRST YEARS OF LIFE

What does a human baby’s brain
look like after its three trimesters of
Brain Facts 49
7 Infant, Child & Adolescent Brain
development in the womb? After birth,

the baby’s brain continues to grow and
develop. The average brain-weight of
a newborn human baby is about 370
grams (or 13 ounces), just slightly less
than a pound. Compare that to the
average weight of an adult brain:
3 pounds, with about 86 billion neu-
rons. The newborn baby’s brain is the
product of 40 weeks of brain devel-
opment, and its rapid development
continues after birth.
How fast does an infant’s brain
grow? Immediately after birth, the
growth rate of the whole brain is about
1 percent per day. The rate slows as the
Gennatas, et al. The Journal of Neuroscience, 2017.
baby ages, reaching about 0.4 percent

per day by 3 months after birth. By the
time a baby is 90 days old, its overall
brain volume is 64 percent larger than
it was at birth, with the fastest-growing
brain region, the cerebellum, more
than double its volume at birth. Not
only is the cerebellum the brain region
with the most neurons, but it helps Researchers use MRI scans to study how your age and sex affect the size and shape of your
with learning motor skills and move- brain. They found distinct differences in the density, volume, mass, and thickness of the gray
matter in the brains of young people and adolescents.
ments — highly important for babies
learning to grab things and eat food.
The overall increase in brain volume
is the result of a large number of brain
cells growing, multiplying (proliferat-
ing), maturing (differentiating), and
migrating to different brain regions.
During the first three months of life,
the number of neurons in the cortex
increases by 23–30 percent. The den-
drites and axons of these neurons grow
longer and make many connections, or
synapses (synaptogenesis), which also
makes the brain bigger. Adding even
more to the brain volume, cells known
as glia grow, multiply, and provide
myelination (by oligodendrocytes) —
NIH.
in fact, the brain’s white matter looks

white due to all the myelin-wrapped The brain goes through many changes during adolescence, including the maturation of the
cerebral cortex — the outer layer of the brain that is important for reasoning and abstract
nerve fibers in those areas. By the time thinking. This image shows how this area develops during this time, with the blue color
a child is 5 years old, the brain has indicating areas that are more mature.

Infant, Child & Adolescent Brain 7
reached about 90 percent of its adult seeing parents’ faces, hearing their subjects over extended periods of time.
size, which still leaves plenty of room voices, and being held in its parents’ Longitudinal studies are especially
to grow during childhood, adoles- arms — provide important sensory important because they can reveal how
cence, and early adulthood. inputs that shape connections be- early life events and environment can
The number of connections tween neurons. During these critical affect outcomes later in life, like edu-
between neurons (synaptic density) periods of development, inputs from cation or risk for disease. These studies
increases rapidly during the first couple sensory, motor, and even emotional are also helpful for understanding how
years of life, so that a 2-year-old’s brain aspects of life experiences affect how a healthy brain changes between early
has 50 percent more synapses than an the brain develops and adapts to the childhood and adolescence. Adoles-
adult brain, although it is only about 80 given environment. Both genes and cence can be thought of as a second
percent the size of an adult brain. That’s environment exert strong influenc- “critical period” as the more complex
far too many synapses for the brain to es during critical periods, forming functions of the brain develop and can
maintain, as synapses use energy and neural circuits that affect learning and be influenced by environment
resources. Therefore, during early child- behavior. Part of shaping these con- and experience.
hood, the brain begins to reduce the nections involves neuronal cell death Images of the adolescent brain ob-
number of synapses and fine-tune the and synaptic pruning, which occur tained by magnetic resonance imaging
connections — this synaptic pruning in the embryo and in early postnatal (MRI) show an increase in white matter
process is shaped by toddlers’ experi- life. Interestingly, changes in neural volume, especially in the corpus callo-
ences as they grow. Just as pruning rose connections during critical periods sum — a large bundle of myelinated
bushes gets rid of the dying or weaker coincide with high rates of learning, fibers that connects the brain’s right
branches so that nutrients go to the such as a toddler learning to run or to and left cerebral hemispheres. The
newer branches and enable new roses to speak multiple languages. growth of the corpus callosum may
bloom and flourish, synaptic pruning explain enhanced learning capacity
allows weaker connections to diminish INTO ADOLESCENCE in adolescence, due to the increasing
while stronger synapses that are activat- What’s going on in the typical connections. Enhanced connections,
ed more often will grow and stabilize. teenage brain? It’s no surprise changes in the brain’s reward systems,
that many changes are happening and changes in the balance between
EXPERIENCE SHAPES during adolescence, in the body as frontal and limbic brain regions can all
THE BRAIN well as the brain. But what’s amazing contribute to teenage behaviors such
Are the brains of human is the brain’s capacity to learn during as increased risk taking and sensation
babies similar to the brains of these teenage years. The teen brain is seeking — also aspects of an enhanced
other baby animals such as kittens and like a big ball of clay, ready to change learning ability.
ducklings? Compared to other ani- and be molded by new experiences Unfortunately, this can be a
mals, humans are actually born with — but it is also very messy. During double-edged sword, as the associated
less developed brains, and human this time, more synaptic pruning risk taking and sensation seeking also
brains take longer to mature. Squirrel occurs, with stronger connections increase the risk of addiction. Some
monkeys, for example, reach their beating out weaker ones in a process regard addiction as a type of acquired
adult brain size at 6 months old. called competitive elimination. At the learning disorder, pointing to the over-
Rather than developing more fully in same time, the brain is improving its lap between brain regions involved in
the womb or egg, human brains grow connections, with neurons extending addiction and those supporting learn-
and develop extensively after birth. their dendritic branches and myelin- ing, memory, and reasoning. Frequent
One advantage is that our developing ation of axons increasing, especially in drug use during adolescence is asso-
brains are more easily shaped by the frontal lobes. ciated with damage to brain regions
environment and experience, which In exploring how the brain chang- important for cognitive functions such
helps us adapt appropriately to the es during the aging process, scientists as memory, attention, and executive
surrounding environment. are particularly interested in longi- functioning. Studies using MRI to
A baby’s early life experiences — tudinal studies, which track human measure brain volume and a technique

7 Infant, Child & Adolescent Brain
called diffusion tensor imaging (DTI) lobe is important for executive func- stimuli are the sounds of adult songs,
to study quality of white matter show tioning, which includes attention, which shape the normal development
that alcohol and other drugs of abuse response inhibition, emotion, organi- of the bird’s ability to sing accurately.
may cause significant changes in gray zation, and long-range planning. The Experience-dependent plasticity
and white matter in adolescents. Com- late maturation of the frontal lobe describes continuing changes in the
pared to a healthy adolescent brain, might explain characteristics of a “typ- organization and specialization of a
adolescents who used alcohol had re- ical teenager,” such as a short attention person’s brain regions as a result of
duced gray matter volume and reduced span, blurting out whatever comes to life experiences that are not universal
white matter integrity. Another study mind, and forgetting to do homework. or anticipated. These include skills
used fMRI to measure brain activity However, none of this means that the that develop throughout life, with no
and showed that binge drinking (alco- teenage brain is broken. It is simply critical or optimal period for their ac-
hol) during adolescence was associated experiencing a critical period of devel- quisition. For example, not everyone
with lower brain activity, less sustained opment that also opens the brain to will play the violin, but violinists of-
attention, and poorer performance on millions of new learning opportunities. ten show greater cortical development
a working memory task. in the brain region associated with the
When do we become adults? The PLASTICITY fingers of their left hand. Using an ex-
definition of adulthood varies with the Plasticity is the ability of the citing technology called two-photon
context — social, judicial, educational. brain to modify itself and imaging, scientists can observe living
Neuroscience research indicates that adapt to environmental challenges, neurons in animals with a microscope
human brains continue to develop un- including sensory inputs. Without and track their growth after various
til we are about 30 years old. Different plasticity, critical periods would not experiences. The results of these
brain regions show different rates of exist because the brain could not studies indicate that experience-de-
growth and maturation. For example, respond to environment and experi- pendent plasticity occurs not only
MRI studies show that the gray matter ence. Plasticity is not unique to during critical periods but also during
density of most brain regions declines humans, but our brains’ capacity to adulthood — apparently, our brains
with age; however, gray matter densi- adapt is a defining attribute of are always changing in response to
ty increases in the left temporal lobe human beings. Plasticity has been our experiences.
(important for memory and language) categorized as experience-expectant Recent insights into brain devel-
until age 30. Brain development in or experience-dependent. opment hold considerable promise
20-somethings also includes changes Experience-expectant plasticity for new treatments of neurological
in where myelination occurs. Remem- refers to integrating environmental disorders, traumatic brain injury, and
ber that myelination is important for stimuli into normal developmental learning disabilities, and could help us
efficiently conducting electrical signals patterns. Being exposed to certain understand aging as well. If scientists
along axons, and myelin protects axons common or universal environmental can design an approach to manipulat-
from damage. Earlier in life, more experiences — for example, hearing ing adult plasticity — whether with
myelination is found in the visual, language, seeing faces, or being held drugs or with therapies that involve
auditory, and limbic cortices. Closer to — during limited critical, or sensitive, rewiring neural circuits — it might be
30, the frontal and parietal neocortices periods of development is essential for possible to correct problems that result
become more myelinated, which helps healthy brain maturation. An example from mistimed critical periods or sim-
with working memory and higher comes from the bird world; finches ilar dysfunctions. A better understand-
cognitive functions. that do not hear adult songs before ing of normal brain function during
These frontal lobe regions are the sexual maturation will not learn to each developmental stage could be the
last brain regions to develop, gaining sing as well as other members of their key to finding age-specific therapies for
more myelin later in life. The frontal species. In this case, the environmental many brain disorders.

CHAPTER
8
Adult & T
he previous chapter described
how your brain changes as
you grow — in overall size,
number of cells, myelination, and
Aging Brain synapse formation — even continuing

to develop well beyond your teenage
years. In fact, recent research suggests
that maturation is still occurring in the
third decade of your life. So when does
a human brain finally reach maturity?
What is the structure of a fully-formed
adult brain? And what can it do that a
developing brain cannot?
THE ADULT BRAIN

An adult brain differs from an
adolescent brain in many ways.
Between childhood and adulthood, a
human brain loses gray matter as
excess neurons and synapses are
pruned away, although the rate of loss
slows down by a person’s late 20s. At
the same time, some brain regions
strengthen their connections with each
other, and the major nerve tracts
become wrapped in insulating myelin,
which increases the brain’s white
matter. Around age 40, the white
matter in the human brain has reached
its peak volume.
Much of the added white mat-
ter represents increased connections
between widely separated brain areas.
During childhood and adolescence,
most brain networks are locally
organized, with areas near each other
working together to accomplish a cog-
nitive task. In adulthood, the brain’s
organization is more widely distribut-
ed, with distant areas connected and
working together.
The most important brain area to
become fully “wired up” in adulthood
is the prefrontal cortex (PFC) — the
front (anterior) portion of the frontal
lobe. This area handles many of our
higher-level cognitive abilities such
Brain Facts 53
8 Adult & Aging Brain
Desmazieres, et al. Journal of Neuroscience, 2014

As the brain matures, a fatty substance called myelin wraps around axons to speed up electrical transmission. This image shows axons
wrapped in myelin, with exposed areas in the middle called nodes of Ranvier.
as planning, solving problems, and ligence, which deals with vocabulary and disability are not. In fact, neu-
making decisions. It is also important and knowledge of facts, increases until roscientists believe our brains can
for cognitive control — the ability to about age 50. Some scientists speculate remain relatively healthy as we age.
suppress impulses in favor of more that there is no single age at which Pronounced decline in memory and
appropriate responses. Adult brains all (or even most) of our cognitive cognitive ability, once thought to be
are better “wired up” for cognitive functions are at their peak. part of normal aging, are now recog-
control than are adolescent brains, in nized as separate disease processes in
which decision-making is more highly WHAT IS AGING? the aging brain. Although the brain
influenced by emotions, rewards, and Normal vs. Pathological Aging loses some neurons as we age, a wide-
social influences. Aging is a dynamic, gradual pro- spread and profound loss of neurons
Intelligence also peaks during early cess. While it can be characterized by is not part of normal aging.
to middle adulthood, roughly ages 25 resilience in both physical and neuro- Nonetheless, some mental decline
to 60. However, different cognitive logical health, too often aging increas- is normal. The continuous process
abilities have distinctive patterns of es the risk of injury and disease. One of aging involves subtle changes in
maturation. Fluid intelligence, which such risk is dementia, a decline in brain structure, chemistry, and func-
includes abilities like solving problems cognitive ability that interferes with tion that commonly begin in midlife.
and identifying patterns, peaks around a person’s day-to-day functioning. Some studies suggest that cognition
age 30. By contrast, crystallized intel- While aging is inevitable, dementia starts declining as early as the 20s and

Adult & Aging Brain 8
30s, while other studies indicate that filter out distractions is called selective are among the areas that demonstrate
cognition improves into the 50s or attention. Another type of attention, the most pronounced declines in both
60s, before declining. A growing area divided attention, refers to the ability volume and cortical thickness. These
of neuroscientific research focuses on to focus on two tasks at the same time. are the areas that took longest to reach
understanding “healthy aging,” which Activities that require this type of split maturity. This finding has led to a “last
includes lifestyle choices, such as diet focus — such as holding a conversation in, first out” theory of brain aging,
and exercise, which support cognitive while driving — also become more which holds that the last parts of the
health throughout life. challenging with age. brain to develop are the first to deteri-
orate. Interestingly, studies of age-re-
HOW THE BRAIN CHANGES Structural Changes lated changes in white matter support
Cognitive Changes All of these alterations in cognitive this hypothesis. The first of the brain’s
Subtle changes in cognition are a ability reflect changes in the brain’s long-distance fibers to develop are
normal part of the aging process, with structure and chemistry. As we enter the projection fibers that connect the
memory decline being the most com- midlife, our brains change in subtle but cortex to lower parts of the brain and
mon. However, not all types of mem- measurable ways. Studies using brain spinal cord. Fibers connecting diffuse
ory are affected; declarative memory imaging techniques have revealed that areas within a single hemisphere —
declines with age, but nondeclarative total brain volume begins to decline association fibers — are the last to
memory remains largely intact. when people are in their 30s or 40s, reach maturity, and show the steepest
As you learned in Chapter 4, and starts declining at a greater rate functional declines with age.
declarative memory includes autobi- around age 60. However, studies of in-
ographical memory of life events, called dividual brain regions suggest that the Neuronal Changes
episodic memory, and memory of volume loss is not uniform throughout The aging brain also under-
learned knowledge, or semantic mem- the brain. Some areas appear to shrink goes numerous changes at
ory. Nondeclarative memory includes more, and faster, than other areas. synapses. Although the synaptic
procedural memory like remembering The prefrontal cortex, cerebellum, and changes are selective and subtle, their
how to ride a bike or tie a shoe. hippocampus show the biggest losses, effect on cognitive decline is believed
Working memory — the abili- which worsen in advanced age. to be greater than the effects of
ty to hold a piece of information in Several changes at the level of structural and chemical changes. In
mind and manipulate it (for exam- individual neurons can also contribute the prefrontal cortex and hippocam-
ple, looking up a phone number and to the decreased volume seen in aging pus, scientists have observed alter-
reciting it as you dial) — also declines brains. The changes in aging are due ations in dendrites, the branching
with age. Some studies suggest that a to shrinking neurons, retraction and processes that receive signals from
slow decline starts as early as age 30. decreased complexity of dendrites, and other neurons. With increasing age,
Working memory, an example of the loss of myelin. In contrast, the volume the dendrites shrink, their branches
fluid intelligence mentioned above, is loss in adolescence is primarily driven become less complex, and they lose
a set of cognitive skills that depend on by synaptic pruning and the death of dendritic spines, the tiny protuberanc-
rapid processing of new information excess cells. es that receive chemical signals.
rather than on stored knowledge. Oth- Our cerebral cortex, the wrinkled A study in rhesus monkeys ob-
er aspects of fluid intelligence, such as outer layer of the brain containing served that the aging process targets
processing speed and problem-solving, neuron cell bodies, also thins as we a certain class of spines called thin
also decrease with age. age. Cortical thinning follows a pat- spines. These small, slender pro-
Certain aspects of attention can tern similar to volume loss, with some tuberances are also highly plastic
also become more difficult as our brains regions of the brain affected more than structures, extending and retracting
age. For example, it might be harder to others. Thinning is especially pro- much more rapidly than the larger
focus on what friends are saying when nounced in the frontal lobes and parts “mushroom” class of spines. This has
we’re in a noisy restaurant. The ability of the temporal lobes. led scientists to speculate that thin
to focus on a particular stimulus and The temporal and frontal lobes spines might be involved in working

memory, which requires a high degree less dopamine is synthesized in the your body contains organelles called
of synaptic plasticity. The loss of thin aged brain, and there are fewer re- mitochondria, which function a bit
dendritic spines could impair neuro- ceptors to bind the neurotransmitter. like cellular power plants, carrying
nal communication and contribute Less robust evidence indicates that out chemical reactions that provide
to cognitive decline. So far, direct the amount of serotonin might also energy for cell use. Some of these
evidence of their role in cognitive decline with age. metabolic reactions produce harmful
decline is lacking, and more studies byproducts called free radicals, highly
are needed. WHY DOES THE BRAIN AGE? reactive molecules which, if left un-
Finally, the formation of new From cortical thinning to the checked, can destroy fats and proteins
neurons also declines with age. loss of dendritic spines, you’ve vital to normal cell function and can
Although neurogenesis was once seen how the brain ages. But what damage DNA as well.
believed to halt after birth, we now causes these changes? Many different Your body has natural defense
know of two brain regions that con- theories have been advanced to mechanisms to neutralize free radi-
tinue to add new neurons through- explain why neurons, and cells in cals. Unfortunately, these mechanisms
decline with age, leaving aging tissues
more vulnerable to oxidative damage
by the free radicals. Studies of brain
cells have shown that damage to their
Many different theories have been

mitochondrial DNA accumulates with
age. In addition, the brains of people
with mild cognitive impairment and
Alzheimer’s disease show more signs
advanced to explain why neurons, of oxidative damage than the brains of
healthy people. Studies in rodents also
and cells in general, age. link increased oxidative damage to
memory impairments.
Your brain is one of the most
metabolically active organs, demand-
ing around 20 percent of the body’s
fuel. Its enormous energy require-
out life: the olfactory bulbs and the general, age. One possibility is that ments might make the brain even
dentate gyrus of the hippocampus. changes in gene expression play a role. more vulnerable than other tissues
Studies suggest that the rate of neu- Researchers have found that genes to the metabolic changes that occur
rogenesis plummets with age in mice, important for synaptic plasticity are in aging. While the brain’s energy
but recent human studies suggest a expressed less in the brains of older demands remain high, its energy
more modest decline. It is not yet people than in the brains of younger supply can no longer keep pace; the
clear whether neurogenesis apprecia- adults. The underexpressed genes also brain’s ability to take up and use glu-
bly affects cognition in the aging hu- showed more signs of damage. cose diminishes and mitochondrial
man brain, but mouse studies indicate metabolism declines.
that strategies that boost neurogenesis Oxidative Stress
can enhance cognitive function. and DNA Damage Immune Dysfunction
DNA damage that accumulates Immune dysfunction often occurs
Chemical Changes over a lifetime could contribute in conjunction with the metabolic
The amount of neurotransmit- to aging processes throughout the changes seen in aging. Microglia, the
ters and the number of their recep- brain and body, and DNA damage brain’s resident immune cells, per-
tors might also decline with age. due to oxidative stress has received a form many important jobs: defending
Several studies have reported that great deal of attention. Every cell in against pathogens, cleaning up cellular

Adult & Aging Brain 8
example, could contribute to, or even

drive, many changes seen in the
aging brain.
HEALTHY AGING
We have learned how
the brain changes with
age and why these changes can occur.
Now let’s turn our attention to a
growing field in neuroscience that
explores ways to slow these changes
and preserve healthy brain function.
Diet and Exercise

Strong evidence now suggests
that habits and choices that keep your
body healthy also benefit your mind.
Poor cardiovascular health puts a
person at increased risk of age-related
cognitive impairment. Diets rich in
vegetables, fruits, and whole grains,
and low in meat and dairy products,
Synapses begin to weaken as a person ages, which can contribute to normal
can reduce cardiovascular risk factors
cognitive decline. linked to cognitive impairment, such
as high blood pressure and high levels
debris, and helping maintain and re- break down and recycle damaged of LDL cholesterol. Indeed, observa-
model synapses. These inflammatory proteins and molecules, using a pro- tional studies have found that people
responses are protective, but a process that is usually efficient but not who follow plant-rich diets such as
longed inflammatory state is harmful perfect. Over time, damaged mole- the Mediterranean diet or Dietary
to brain health. Microglia become cules can build up in cells and prevent Approaches to Stop Hypertension
more reactive with age, increasing the them from functioning normally. (DASH) are less likely to develop
inflammatory response in the brain Because neurons in the brain are not cognitive decline and dementia.
while also damping production of replaced as often as cells in other Specific nutrients have been linked
helpful anti-inflammatory molecules. parts of the body (for example, bone to improved cognitive performance
Mouse studies suggest that excessive marrow, intestinal lining, hair folli- and lower rates of dementia. Anti-
microglial activity also contributes to cles), brain cells might be even more oxidants, such as vitamins C and E,
cognitive impairments. vulnerable to this buildup of damaged flavonoids, and omega-3 fatty acids
molecules. Also, the cellular ma- have received considerable attention,
Impaired Protein Recycling chinery involved in breakdown and with observational studies showing
We know that excessive buildup recycling processes degrades with age, that high dietary intake of these
of abnormal proteins in the brain reducing the efficiency of the “waste compounds is beneficial. However,
contributes to age-related neurode- removal” systems. the results of lifestyle intervention
generative diseases like Alzheimer’s Finally, remember that changes studies using supplements have been
and Parkinson’s. Buildup of proteins in the aging brain occur within the more mixed. Finally, caloric restriction
and other cell components can also context of other changes throughout — substantially reducing the number
contribute to cellular degeneration the body. Researchers speculate that of calories eaten without leading to
in the healthy brain. Cells normally worsening cardiovascular health, for malnutrition — has been linked to

sedentary mice, and they perform bet-

ter on learning and memory tests. Ex-
ercise can also improve blood flow and
increase production of neurotrophic
factors that support new neurons and
synapses. For humans, starting exercise
later in life can be beneficial, but the
studies suggest that adopting an exer-
cise program earlier in life could yield
even more neuroprotective benefits.
Mental Stimulation
and Social Networks
Mental stimulation and large so-
cial networks can also improve cogni-
tive function in aging. In lab studies,
mice housed in cognitively stimulat-
ing environments with many oppor-
tunities for social interaction perform
better on learning and memory tests
as they age compared to mice housed
in standard cages. Much like physical
iStock.com/artyme83.
exercise, cognitive stimulation appears
to enhance neuroplasticity by increas-
ing neurogenesis and boosting levels
Exercise has been shown to increase neurogenesis in the adult brain, and can slow the
of important neurotrophic factors.
cognitive decline associated with aging. People who perform cognitive-
ly-demanding work or engage in
improved cognitive health as well as a cortical thinning and less shrinkage in stimulating activities such as reading,
longer lifespan. the hippocampus. solving puzzles, or playing a musical
Growing evidence shows that Exercise exerts its neuroprotec- instrument have lower rates of cog-
aerobic exercise can improve cognitive tive effects in the brain by improving nitive decline with aging. An active
function and offset some of the de- neuroplasticity — the brain’s ability to social life has also been shown to be
clines seen in aging. Numerous studies form and reorganize connections be- beneficial for cognition as we age.
have found that people who engage tween neurons in response to changes Neuroscientists have learned a
in regular physical activity show in behavior and environment. Scien- lot about the aging brain — how it
improved learning, improved mem- tists also believe that exercise increases changes, why it changes, and how
ory, and a reduced risk of developing neurogenesis (the formation of new to maintain healthy cognitive func-
dementia. Physical activity might even nerve cells) which, in turn, enhances tioning as we age. Even so, many
slow the progression of Alzheimer’s neuroplasticity. Evidence from rodent questions remain. Answers to those
disease and dementia, and higher levels studies confirms that exercise increases questions could identify new strate-
of physical activity have been linked neurogenesis: Older mice allowed to gies for protecting the brain, not only
to improvements in some markers of run on a wheel have higher rates of in our later years, but throughout
structural brain health, such as reduced neurogenesis in the hippocampus than our lives.

CHAPTER
9
Brain States H
ave you ever considered the
ups and downs that occur
during your day? Speaking
literally, you are up and awake during
the day and lying down sleeping at
night. Speaking figuratively, ups and
downs could mean that you experi-
ence periods of elevated alertness and
arousal compared with your mood when
you are tired or relaxed. Asleep, awake,
aroused, and relaxed are different brain
states, meaning that the brain’s activity
is different during each of these peri-
ods. Scientists have looked deep inside
the brain to understand what sleep is
and how rest differs from being alert.
This research is especially important
for people like doctors, pilots, and shift
workers who sometimes must focus and
make important decisions with very little
sleep. Research on brain states can also
help people who have disorders of sleep,
attention, and learning.
SLEEP
How many hours of sleep do you
get every night? Most people spend
one-third of their lives asleep. While
that might appear to be a lot of time
spent doing nothing, our brains are
active while we rest each night. The
activity in our brains during sleep is
important for brain health and for
solidifying memories.
Most people feel tired and un-
able to focus if they don’t get enough
sleep. In some cases, too little sleep
can impair a person’s driving as much
as drinking alcohol. The long-term ef-
fects of lacking sleep also involve many
health risks. Several studies in humans
have revealed that sleep-deprived
people are at increased risk for a wide
range of health issues including diabe-
tes, stress, obesity, high blood pres-
sure, anxiety, cognitive impairment,
and depression.
Brain Facts 59
9 Brain States
This chart shows the brain waves of an individual being recorded by an EEG machine during a night’s sleep. As the person falls asleep,
the brain waves slow down and become larger. Throughout the night, the individual cycles though sleep stages, including REM sleep,
where brain activity is similar to wakefulness.
Brain Activity During Sleep synchronized way from a depolarized their electrical states is less positive (or
Scientists can measure the brain’s (more excitable) state to a hyperpo- negative) than if they acted in synchro-
electrical activity using electroenceph- larized (less excitable) state and back ny. Paradoxically, the fast, waking-like
alography (EEG). Electrodes attached again. These slow waves appear to EEG activity during REM sleep is ac-
to the scalp detect and record the net be important to sleep function — companied by atonia, a loss of muscle
electrical activity of hundreds of thou- the longer a person stays awake, the tone causing the body to become tem-
sands of cortical nerve cells. When a more slow waves they will experience porarily paralyzed. The only muscles
neuron is active, ions move in and out during the SWS state. Slow waves remaining active are those that enable
of the cell, altering the electrical charge become less frequent the longer the breathing and control eye movements.
across the cell membrane. An EEG de- person is asleep. If awakened during Oddly enough, the neurons of our
tects the net electrical charge produced SWS, most people recall only frag- motor cortex fire as rapidly during
when neurons increase and decrease mented thoughts, not active dreams. REM sleep as they do during waking
their activity as a group, in synchrony. Have you ever seen a cat dream- movement — a fact that explains why
The results are “brain waves” — the ing — twitching its whiskers or paws movements like a kitten’s twitching
cyclic rising and falling of brain activ- while it sleeps? Dreaming happens paws can coincide with dreams.
ity that can be important indicators of mainly during REM sleep, which takes During the night, periods of
brain function. In sleep studies, scien- its name from the periodic rapid eye SWS and REM sleep alternate in
tists now recognize two main states: movements people make in this state. 90-minute cycles with 75–80 minutes
slow wave sleep (SWS) and rapid eye Brain activity recorded during REM of SWS followed by 10–15 minutes
movement sleep (REM). looks very similar to EEGs recorded of REM sleep. This cycle repeats,
SWS gets its name from the while awake. EEG waves during REM typically with deeper and longer peri-
high amplitude, low frequency, sleep have much lower amplitudes ods of REM sleep towards morning.
brain waves in EEG recordings. than the SWS slow waves, because To study sleep disorders, researchers
The high amplitude of slow waves neuron activity is less synchronized often use mice that have sleep struc-
indicates that many cortical neu- — some nerve cells depolarize while tures qualitatively very similar to hu-
rons are switching their activity in a others hyperpolarize, and the “sum” of mans; however, rodents have shorter

Brain States 9
and more frequent sleep episodes can be activated by insulin-induced tone — hallmark signs of REM.
lasting 3–30 minutes (sometimes lon- low blood sugar. Thus, they are During SWS, the brain systems
ger). Rodents also sleep more during involved in energy metabolism. Given that keep us awake are actively sup-
the day and are more active at night. these functions, it comes as no surprise pressed. This active suppression of
Compare that to human adults, who that orexin-producing neurons are arousal systems is caused by the ven-
are typically more active during the important for preventing a sudden trolateral preoptic (VLPO) nucleus, a
day and have one sleep episode at transition to sleep; their loss causes group of nerve cells in the hypothala-
night lasting about 8 hours. narcolepsy, as described below. Orexin mus. Cells in the VLPO release the in-
neurons also connect to hypothalamic hibitory neurotransmitters galanin and
Sleep Regulation neurons containing the neurotransmit- gamma-aminobutyric acid (GABA),
How does the brain keep us ter histamine, which plays a role in which can suppress the arousal sys-
awake? Wakefulness is main- staying awake. tems. Damage to the VLPO nucleus
tained by the brain’s arousal systems, The balance of neurotransmitters causes irreversible insomnia.
each regulating different aspects of the in the brain is critically important for
awake state. Many arousal systems are maintaining certain brain states. For Sleep-Wake Cycle
in the upper brainstem, where neurons example, the balance of acetylcholine Two main factors drive your body
connecting with the forebrain use the and norepinephrine can affect wheth- to crave sleep: the time of day or night
neurotransmitters acetylcholine, er we are awake (high acetylcholine (circadian system) and how long you
norepinephrine, serotonin, and and norepinephrine) or in SWS (low have been awake (homeostatic system).
The homeostatic and circadian systems
are separate and act independently.
The circadian timing system is
regulated by the suprachiasmatic
nucleus, a small group of nerve cells
The balance of neurotransmitters in the hypothalamus that functions

as a master clock. These cells express
“clock proteins,” which go through a
in the brain is critically important for biochemical cycle of about 24 hours,
setting the pace for daily cycles of
maintaining certain brain states. activity, sleep, hormone release, and
other bodily functions. The master
clock neurons also receive input
directly from the retina of the eye.
Thus, light can reset the master clock,
adjusting it to the outside world’s
glutamate to keep us awake. Orexin- acetylcholine and norepinephrine). day/night cycle — this explains how
producing neurons, located in the During REM, norepinephrine re- your sleep cycles can shift when you
hypothalamus, send projections to the mains low while acetylcholine is high, change time zones during travel. In
brainstem and spinal cord, the thala- activating the thalamus and neocortex addition, the suprachiasmatic nucleus
mus and basal ganglia, as well as to the enough for dreaming to occur; in sends signals through different brain
forebrain, the amygdala, and dopa- this brain state, forebrain excitation regions, eventually contacting the
mine-producing neurons. In studies of without external sensory stimuli pro- VLPO and the orexin neurons in the
rats and monkeys, orexin appears to duces dreams. The forebrain becomes lateral hypothalamus, which directly
exert excitatory effects on other arousal excited by signals from the REM regulate arousal.
systems. Orexins (there are two types, sleep generator (special brainstem What happens in the brain when
both small neuropeptides) increase neurons), leading to rapid eye move- we don’t get enough sleep? The second
metabolic rate, and their production ments and suppression of muscle system that regulates sleepiness is the

9 Brain States
homeostatic system, which makes you

feel sleepy if you stay awake longer
than usual. One important sleep
factor is a chemical in the brain called
adenosine. When you stay awake for
a long time, adenosine levels in the
FPO
brain increase. The increased ade-
nosine binds to specific receptors on
nerve cells in arousal centers to slow
cellular activity and reduce arousal.
Adenosine can increase the number of
slow waves during SWS. As you get
Simon Fraser University.
more sleep, adenosine levels fall and

slow waves decrease in number. Caf-
feine acts as a stimulant by binding to
adenosine receptors throughout the
brain and preventing their interaction Electroencephalography measures brain activity through sensors placed on the head. It can
with adenosine. As a result, in the record how the brain reacts to all kinds of stimuli and activities, including sleep.
presence of caffeine, fewer receptors
are available for the slowing influence initially; others fall asleep, then awak- with sleep apnea require breathing
of adenosine. en part way through the night and machines to keep their airway open.
People often say they need to can’t fall back asleep. Several common One such device, called a continuous
“catch up on sleep.” But can you really disorders, listed below, disrupt sleep positive airway pressure or “CPAP”
make up for lost sleep? Normally, the and prevent people from getting an machine, uses a small mask that fits
homeostatic and circadian systems adequate amount of sleep. over the nose to provide an airstream
act in a complementary fashion to Daytime sleepiness (not narcolep- under pressure during sleep. In some
produce a normal 24-hour cycle of sy), characterized by excessive feelings cases, people need surgery to correct
sleep and wakefulness. Nonetheless, of tiredness during the day, has many their airway anatomy.
activating the brain’s arousal system causes including sleep apnea (see be- REM sleep behavior disorder
can keep us awake even after a long pe- low). Increased daytime sleepiness can occurs when nerve pathways in the
riod of wakefulness — for example, a increase the risk of daytime accidents, brain that prevent muscle movement
late-night study session to prepare for especially car accidents. during REM sleep do not work.
an important exam. In normal circum- Sleep apnea occurs when the air- Remember that dreaming happens
stances, the homeostatic system will way muscles of the throat relax during during REM sleep, so imagine people
respond to the loss of sleep by increas- sleep, to the point of collapse, closing literally acting out their dreams by
ing the duration of ensuing sleep and the airway. People with sleep apnea getting up and moving around. This
increasing the number of slow waves have difficulty breathing and wake up can be very disruptive to a normal
during the SWS episodes. As noted without entering the deeper stages of night’s sleep. The cause of REM be-
above, this rebound slow wave activity SWS. This condition can cause high havior disorder is unknown, but it is
correlates with the previous time spent blood pressure and may increase the more common in people with degen-
awake and is mediated by adenosine. risk of heart attack. Treatments for erative neural disease such as Parkin-
sleep apnea focus on reducing airway son’s, stroke, and types of dementia.
Sleep Disorders collapse during sleep; simple changes The disorder can be treated with
The most common sleep disorder, that may help include losing weight, drugs for Parkinson’s or with a ben-
and the one most people are familiar avoiding alcohol or sedating drugs zodiazepine drug, clonazepam, which
with, is insomnia. Some people with prior to sleep, and avoiding sleeping enhances the effects of the inhibitory
insomnia have difficulty falling asleep on one’s back. However, most people neurotransmitter GABA.

Brain States 9
Narcolepsy: An Example studying neurons that were neighbors Neurotransmitters

of Sleep Disorder Research to orexin neurons to see what hap- During arousal, the brain must de-
Narcolepsy is a relatively pened if the neighboring neurons were vote resources to specific brain regions,
uncommon sleep disorder — activated in narcoleptic mice. Those much as an emergency call center
only 1 case per 2,000 people in the neurons contained melanin-concen- redirects resources like ambulances
United States — in which the brain trating hormone, and stimulating and fire trucks during a fire. Specific
lacks the special neurons that help them (using a technique called opto- types of neurons in the brain regions
control the transition into sleep, so genetics) induced sleep — opposite to involved in arousal release multiple
that the regular cycling is disrupted. the effect of stimulating orexin neu- neurotransmitters, telling the rest of
People with narcolepsy have sleep rons. A balance between the activation the brain and the body to be on alert.
attacks during the day, causing them of orexin neurons and their neighbor- These neurotransmitters are dopamine
to suddenly fall asleep, which is ing neurons could control the tran- (for movement), norepinephrine (for
especially dangerous if they are sition between waking and sleeping. alertness), serotonin (for emotion),
driving. The problem is caused by the These findings will be important in and acetylcholine and histamine,
loss of orexin neurons in the lateral developing treatments for narcolepsy. which help the brain communicate
hypothalamus. People with narcolep- with the body to increase arousal.
sy tend to enter REM sleep very AROUSAL
quickly and may even enter a dream- Think about what happens in Sensory Input
ing state while still partially awake, a your body and mind when you speak While neurotransmitters provide
condition known as hypnagogic in front of a crowd — your brain the internal signals for arousal, external
hallucination. Some people with state is very different from when signals from the outside world — like
narcolepsy also have attacks in which you are asleep. Perhaps you notice the bright lights (visual input) and
they lose muscle tone — similar to changes in your breathing, heart rate, cheering crowds (auditory input) at a
what happens in REM sleep, but or stomach. Maybe your thoughts are stage performance — can also stimu-
while they’re awake. These attacks of racing or panicked. Or maybe you late arousal. Sensory input gets sorted
paralysis, known as cataplexy, can be are energized and excited to perform in the brain region called the thala-
triggered by emotional experiences for your audience. These are exam- mus. Often called a “sensory clearing
and even by hearing a funny joke. ples of the complex brain state house,” the thalamus regulates arous-
Recent research into the mech- called arousal. al, receiving and processing sensory
anisms of narcolepsy has provided Rather than merely being awake, inputs from brain regions important
important insights into the processes arousal involves changes in the body in senses like vision and hearing and
that control the mysterious transitions and brain that provide motivations relaying these inputs to the cortex.
between waking, slow wave sleep, to do an action — teaching a class,
and REM sleep states. Orexin (in the speaking in public, or focusing your Autonomic Nervous System
lateral hypothalamus) is critical for attention. People experience arousal Once the brain is aroused, what
preventing abnormal transitions into daily when searching for food while does the body do? The reticular
REM sleep during the day. In one hungry, or when talking with other activating system, in the brainstem, co-
study, scientists inactivated the gene people (social interaction). Arousal is ordinates signals coming from sensory
for orexin in mice and measured their also important for reproduction and inputs and neurotransmitters to make
sleep patterns. They found that mice for avoiding danger. sense of events in the brain and pass
lacking the orexin gene showed symp- The level of arousal varies across that information to the rest of the
toms of narcolepsy. Similarly, humans a spectrum from low to high. When body. The reticular activating system
with narcolepsy have abnormally low arousal falls below a certain threshold specifically controls the autonomic
levels of orexin levels in their brain we can transition from wake to sleep, nervous system, which affects heart
and spinal fluid. for example. But under heightened rate, blood flow, and breathing. By
Because orexin levels are disrupt- arousal, like intense anxiety, we cannot controlling these automatic body pro-
ed in narcolepsy, scientists also began reach this threshold and we stay awake. cesses, the reticular activating system

9 Brain States
sets up the physical state of arousal, because those same physiological tune your focus to different locations,
bringing important resources like oxy- changes occur during arousal, which times, and topics. Consider the page
gen and nutrients to parts of the body is necessary for being alert and paying you are reading right now. Although
where they are needed. attention. As mentioned previously, you can see the whole page, you focus
Together, the changes that happen the state of arousal calls for reactions on only one line at a time. Alterna-
in the brain and body during arous- to the environment. To make deci- tively, you can turn your attention
al enable us to be alert and focused, sions about what to do, you need to to the past — just minutes ago when
which helps us process information focus on what’s happening in the you were reading about arousal. Or
quickly. Using this information, we environment, especially involving you can ignore the sentences alto-
can choose the appropriate emotional
response or physical action for a
given situation.
Sexual Arousal
Several complex brain systems and
endocrine (hormone) systems contrib-
Scientists recognize two types of
ute to sexual arousal and behaviors, but attention, which involve different brain
the brain regions, neurotransmitters,
and body systems are similar to those processes: voluntary attention and
involved in general arousal. The dis-
tinguishing factor is that sexual arousal involuntary attention.
also involves hormones such as estrogen
and testosterone, which then activate
neurons that release the same neu-
rotransmitters that are released during anything relevant to your goals. For gether and focus on the number of
general arousal. Many human and ani- example, if your goal is to run away times the word “you” occurs on this
mal studies report interactions between from an angry bear, you need to be page. Scientists recognize two types
sex hormones and neurotransmitters alert and pay attention to where of attention, which involve different
dopamine, serotonin, GABA, and you’re running so you don’t trip and brain processes: voluntary (endog-
glutamate. Researchers have also found fall. Scientists have theorized that the enous) attention and involuntary
that brain regions such as the hypo- state of arousal speeds processing and (exogenous) attention.
thalamus, amygdala, and hippocampus improves comprehension of environ- Voluntary attention happens
contain many estrogen and progester- mental details. Otherwise, your brain when you choose what to focus on —
one receptors, and brain regions that would need an infinite amount of like finding a loved one in a crowd.
mediate feelings of reward (nucleus time and energy to process all of its The frontal and parietal cortices of
accumbens) and emotions like pleasure sensory inputs (sounds, sights, smells, the brain are active when you control
(amygdala) motivate sexual behaviors. and other feelings), because the your attention or direct it towards a
Overall, the primary involvement of sex environment is always changing. specific object or location. Involun-
hormones is a key in defining the brain tary attention occurs when something
state of sexual arousal. Focus in the environment (like a sudden
Even with multitasking, it is noise or movement) grabs your atten-
ATTENTION impossible for the brain to process tion. Involuntary attention is a dis-
If you are paying all its sensory inputs. Instead, people traction from your chosen goals and,
attention right now, focus their attention on one thing at in fact, researchers often use distrac-
there should be detectable changes in a time. Attention is a fascinating abil- tor objects in attention experiments.
your heart rate, breathing, and blood ity, because it enables you to have so Distractors can be emotional, like
flow. If that sounds familiar, it’s much control and the ability to fine- pictures of family, or non-emotional

Brain States 9
images that stand out from other objects, as well. Diagnosis of hemine- the functions of its “participating”
stimuli, like a red circle surrounded glect syndrome can be done with a brain regions provide hints about its
by gray squares. Brain regions in the pen and paper. For example, patients purpose. Studies on emotion have
right hemisphere, collectively known can be instructed to draw a copy of revealed that activity in the ventro-
as the ventral frontoparietal network, a picture like a butterfly or a castle, medial PFC is directly related to
form a system that processes new and and those patients with hemineglect how anxious a subject feels while
interesting stimuli that distract you usually draw only the right half of performing a task — suggesting that
from the task at hand. Research on at- the picture or leave out details of the the default mode network may play a
tention can help us understand visual left side. Research on patients with role in regulating emotion and mood.
tasks, learning, child development, hemineglect syndrome contributes to Activity in the dorsomedial PFC (a
and disorders of attention. our understanding of rehabilitation region involved in self-referential
after stroke, as well as the role of the or introspective thoughts) increases
Disorders of Attention right parietal cortex in attention when a person is at rest and day-
Paying attention for long and perception. dreaming. The dorsomedial PFC is
periods of time, such as a also involved in stream-of-conscious-
3-hour lecture, can be difficult for REST: DEFAULT MODE ness thoughts and thoughts about
many people. For some people, even NETWORK oneself in the past, present, or future
focusing for a short time can be hard. What is the difference (autobiographical self ). The roles of
Several disorders that affect the ability between being alert these regions suggest that the default
to pay attention are attention deficit and resting while awake? During times mode network may also function
hyperactivity disorder (ADHD), of rest and relaxation, you’re usually in self-reflection and our sense of
schizophrenia, prosopagnosia, and avoiding heavy thinking or complicat- self in time.
hemineglect syndrome. It may seem ed tasks, and parts of the brain called The posterior brain regions of the
strange to regard schizophrenia as an the default mode network are more default mode network (posterior cin-
attention disturbance, but some active. You may think of the default gulate cortex, lateral parietal cortex,
psychiatric studies suggest that it mode network as a personal lullaby or and precuneus) become more active
involves a failure of selective attention. a playlist that turns on when you are when remembering concrete mem-
Prosopagnosia, or face blindness, is a ready to relax. Activity of the default ories from past experiences. These
cognitive disorder in which a person is mode network decreases (the lullaby brain regions are connected with the
unable to recognize faces — even their gets quieter) when you start doing or hippocampus, which is important for
own family members. The severity of thinking about a demanding task. learning and forming memories. Both
this condition varies, and genetic Human studies using imaging tech- the hippocampus and the default
factors might be involved. Attention niques such as functional magnetic mode network are more active when
disorders have various causes, but we resonance imaging (fMRI) and a person is at rest in the evening and
will focus on hemineglect syndrome, positron emission tomography (PET) less active when waking up early in
caused by damage to the right parietal have identified which brain regions the day. These patterns indicate that
cortex, a brain region important in belong to the default mode network. the default mode network helps to
involuntary attention. These brain areas, which are involved process and remember the events
Between 50–82 percent of pain emotion, personality, introspection, of the day.
tients who suffer stroke in the right and memory, include frontal brain Future studies using electrical re-
hemisphere experience hemineglect regions (ventromedial prefrontal cordings from inside the human brain
syndrome, also known as spatial ne- cortex, dorsomedial prefrontal cortex, can be paired with fMRI to tell us
glect and unilateral neglect. In these and anterior cingulate cortex), as well more about the brain activity patterns
cases, patients with neglect ignore the as the posterior cingulate cortex, lateral of the default mode network and how
left side of their visual field. Some- parietal cortex, and precuneus. brain regions coordinate their activity
times they ignore the left side of the Although the exact role of the during tasks that utilize the functions
body and the left side of individual default mode network is unclear, of this network.

CHAPTER
10
The Body T
he cells of your body are
immersed in a constantly
changing environment. The
nutrients that sustain them rise and fall
in Balance with each meal. Gases, ions, and other

solutes flow back and forth between
your cells and blood. Chemicals bind
to cells and trigger the building and re-
lease of proteins. Your cells digest food,
get rid of wastes, build new tissues,
and destroy old cells. Environmental
changes, both internal and external,
ripple through your body’s physio-
logical systems. One of your brain’s
less-visible jobs is to cope with all these
changes, keep them within a normal
range, and maintain the healthy func-
tions of your body.
The tendency of your body’s tissues
and organ systems to maintain a condi-
tion of balance or equilibrium is called
homeostasis. Homeostasis depends
on active regulation, with dynamic
adjustments that keep the environ-
ment of your cells and tissues relatively
constant. The brain is part of many
homeostatic systems, providing signals
that coordinate your body’s internal
clocks and regulating hormone secre-
tion by the endocrine system. These
functions often involve a region of the
forebrain called the hypothalamus.
CIRCADIAN RHYTHMS
Almost every cell in your body
has an internal clock that tells
it when to become active, when to rest,
and when to divide. These clocks
broker changes in many of the body’s
physiological systems over a 24-hour,
or circadian, period. For example, the
clocks cause faster pulses of peristaltic
waves in your gut during the day and
make your blood pressure dip at night.
But because these clocks are deep
inside your body and cannot detect
daylight, none of them can tell time
The Body in Balance 10
on its own. Instead, daily rhythms are pineal gland secretes melatonin into the are out of sync with day and night.
coordinated by the suprachiasmatic bloodstream at night. Melatonin binds Exposure to the local day/night cycle
nucleus (SCN), a tiny group of to cells in many tissues, and although resets the brain and body, but it can
neurons in the hypothalamus. it has no direct effect on clock gene take several days to get fully resynchro-
Neurons in the SCN act like a met- expression in the SCN, its systemic nized. Circadian rhythms can also be
ronome for the rest of the body, emit- effects seem to reduce alertness and disturbed by situations like late-shift
ting a steady stream of action potentials increase sleepiness. Light exposure trig- jobs or blindness, which decouple nor-
during the day and becoming quiet gers signals that stop melatonin secre- mal daylight signals from wake/sleep
at night. The shift between active and tion, promoting wakeful behaviors. cycles. Long-term circadian disruptions
silent states is controlled by cyclic in-
teractions between two sets of proteins
encoded by your body’s “clock” genes.
Researchers first identified clock genes
Coordinated body clocks enable

in the fruit fly Drosophila melanogaster
and studied how they keep time; since
then, a nearly identical set of genes has
been found in mammals. The SCN also
tracks what time it is based on signals
your body’s physiological systems
it receives from photoreceptors in the
retina, which keeps its activity in sync
to work together at the right times.
with the Earth’s actual day/night cycle.
That little nudge is very important be-
cause, on their own, clock proteins take
slightly more than 24 hours to complete
a full cycle. Studies of animals deprived
of light have discovered that they go to Together, these signals keep all the are associated with health problems
sleep and wake up a bit later each day. body’s clocks synchronized to the same including weight gain, increased rates
An autonomic neural pathway 24-hour cycle. Coordinated body clocks of insomnia, depression, and cancers.
ties the daily rhythmic activity of the enable your body’s physiological systems
SCN directly to other clocks in the to work together at the right times. HORMONES,
body. Neurons in the SCN stimulate an When your body prepares to wake from HOMEOSTASIS,
adjacent region of the brain called the sleep, 1) levels of the stress hormone AND BEHAVIOR
paraventricular nucleus (PVN), which cortisol peak in the blood, releasing Neurons can quickly
in turn sends signals down a chain of sugars from storage and increasing deliver the brain’s
neurons through the spinal cord to the appetite, and 2) core body temperature messages to precise targets in the body.
peripheral organs of the body. You’ve al- begins to drift upwards, raising your Hormones, on the other hand, deliver
ready learned how signals in part of this body’s metabolic rate. These events, messages more slowly but can affect a
neural pathway stimulate orexin neu- synchronized with others, prepare your larger set of tissues, producing large-
rons to regulate the body’s sleep/wake body for a new day’s activity. scale changes in metabolism, growth,
cycle. Related pathways also govern the Desynchronizing the body’s phys- and behavior. The brain is one of the
secretion of melatonin, a hormone that iological clocks can cause noticeable tissues that “listens” for hormonal
influences sleep behaviors. Specifically, and sometimes serious health effects. signals — neurons throughout the
electrical activity originating in the SCN You might have experienced a familiar brain are studded with hormone
enters the PVN’s neural network and example of circadian rhythm distur- receptors — and the brain’s responses
sends signals up to the pineal gland, a bance: jet lag. After crossing many time play an important part in regulating
small pinecone-shaped gland embedded zones in a short time period, a person’s hormone secretion and changing
between the cerebral hemispheres. The patterns of wakefulness and hunger behaviors to keep the body systems in

10 The Body in Balance
equilibrium. The brain regions

involved in hormone release are called
the neuroendocrine system.
The hypothalamus oversees the
production and release of many hor-
mones through its close ties to the pi-
tuitary gland. The paraventricular and
supraoptic nuclei of the hypothalamus
send axons into the posterior part of
the pituitary gland; activation of spe-
cific neurons releases either vasopressin
or oxytocin into capillaries within the
pituitary. Both of these molecules act
as neurotransmitters inside the brain,
but they are also hormones that affect
distant tissues of the body. Vasopressin
(also called antidiuretic hormone) in-
creases water retention in the kidneys
and constricts blood vessels (vasocon-
striction). Oxytocin promotes uterine
contractions during labor and milk
release during nursing.
Other hypothalamic regions send
axons to a capillary-rich area above the
pituitary called the median eminence.
When these neurons are activated,
they release their hormones into the
blood. These releasing (and inhibiting)
hormones travel through local blood
vessels to the anterior pituitary, where The neuroendocrine system maintains homeostasis, the body’s normal equilibrium, and
they trigger (or inhibit) secretion of controls the response to stress. The adrenal gland releases the stress hormones norepineph-
a second specific hormone. Of the rine, epinephrine, and cortisol, which quicken heart rate and prepare muscles for action.
Corticotrophin releasing hormone (CRH) is released from the hypothalamus and travels to the
seven anterior pituitary hormones, pituitary gland, where it triggers the release of adrenocorticotropic hormone (ACTH). ACTH
five are trophic hormones — these travels in the blood to the adrenal glands, where it stimulates the release of cortisol.
travel in the bloodstream to stimulate
activity in specific endocrine glands Many hormones produced by mone levels are narrowly regulated.
(thyroid, adrenal cortex, ovaries, etc.) the pituitary and its target endocrine One of these three-hormone
throughout the body. The remaining glands affect receptors inside the brain cascades regulates reproduction in
two hormones act on non-endocrine — thus, these hormones can alter mammals. Its underlying pattern is the
tissues. Growth hormone stimulates neuronal function and gene transcrip- same in both sexes: 1) gonadotropin-
the growth of bone and soft tissues, tion in the hypothalamus. The effect releasing hormone (GnRH) from the
and prolactin stimulates milk produc- is to reduce the amount of hormone hypothalamus makes the anterior pi-
tion by the breasts. Hormones released released by the hypothalamus when tuitary release 2) luteinizing hormone
from the anterior pituitary influence those circuits become active. These (LH) and follicle stimulating hormone
growth, cellular metabolism, emotion, negative feedback loops enable precise (FSH), which in turn make the gonads
and the physiology of reproduction, doses of hormones to be delivered to secrete 3) sex hormones and start the
hunger, thirst, and stress. body tissues, and ensure that the hor- development of mature eggs or sperm.

The Body in Balance 10
Sex hormones, in turn, attach to brain contains receptors for many of was robbed, trying karaoke for the first
receptors in the hypothalamus and an- these hormones but, unlike pituitary time — has the potential to set them
terior pituitary and modify the release hormones, it does not directly regulate off. Scientists call this reaction the stress
of the hypothalamic and pituitary their secretion. Instead, when these response, and your body turns it on to
hormones. However, sex hormones hormones bind to receptors on neu- some degree in response to any external
regulate these feedback loops differ- rons, they modify the output of neural or internal threat to homeostasis.
ently in males and females. circuits, producing behavioral changes
Male sex hormones induce simple that have homeostatic effects. One The Stress Response
negative feedback loops that reduce example of this is a pair of hormones The stress response weaves togeth-
the secretion of gonadotropin-releas- called leptin and ghrelin. er three of the brain’s parallel com-
ing hormone, luteinizing hormone, Leptin and ghrelin change eating munication systems, coordinating the
and follicle stimulating hormone. The behavior by regulating food intake activity of voluntary and involuntary
interplay among these hormones creates and energy balance. Both hormones nervous systems, muscles, and metabo-
a repetitive pulse of GnRH that peaks affect hunger, and both are released lism to achieve one defensive goal.
every 90 minutes. The waxing and wan- in response to changes in an animal’s Messages sent to muscles through
ing of GnRH keeps testosterone levels internal energy stores. However, they the somatic (voluntary) nervous system
relatively steady within body tissues, have different effects on the circuits prime the body to fight or run from
maintains male libido, and keeps the they regulate. Ghrelin keeps the danger (the fight-or-flight response).
testes producing new sperm each day. body fed. Released by the wall of the Messages sent through the autonomic
Female feedback patterns are gastrointestinal tract when the stom- (involuntary) nervous system redirect
more complex. Over the course of the ach is empty, ghrelin activates hunger nutrients and oxygen to those mus-
month-long menstrual cycle, female sex circuits in the hypothalamus that drive cles. The sympathetic branch tells the
hormones exert both positive and nega- a search for food. Once the stomach is adrenal medulla to release the hor-
tive feedback on GnRH, FSH, and LH. full, ghrelin production stops, reduc- mone epinephrine (also called adren-
When circulating levels of the ing the desire to eat. In contrast, leptin aline), which makes the heart pump
female sex hormones estrogen and helps maintain body weight within a faster and relaxes the arterial walls that
progesterone are low, rising follicle set range. Leptin is produced by fat supply muscles with blood so they can
stimulating hormone levels trigger egg cells and is released when fat stores are respond more quickly. At the same
maturation and estrogen production. large. When it binds to neurons in the time, the autonomic system’s parasym-
Rising estrogen levels induce luteiniz- hypothalamus, leptin suppresses the pathetic branch restricts blood flow
ing hormone levels to rise. As the levels activity of hunger circuits and reduces to other organs including the skin,
of female sex hormones rise, they exert the desire to eat. As fat stores are used gonads, digestive tract, and kidneys.
negative feedback on FSH secretion, up, leptin levels decline, driving be- Finally, a cascade of neuroendocrine
limiting the number of eggs that ma- havior that makes an animal eat more hormones originating in the hypothal-
ture in a month, but positive feedback often and replenish its fat stores. amus and anterior pituitary circulates
on LH, eventually producing the LH in the bloodstream, affecting processes
surge that triggers ovulation. After STRESS like metabolic rate and sexual func-
ovulation, high serum levels of sex hor- Your body reacts in stereotyped tion, and telling the adrenal cortex to
mones again exert negative feedback on ways when you feel threatened. You release glucocorticoid hormones —
GnRH, FSH, and LH which in turn breathe faster, your heartbeat speeds like cortisol — into the blood.
reduces ovarian activity. Levels of fe- up, your muscles tense and prepare Glucocorticoid hormones bind to
male sex hormones therefore decrease, for action. These reactions may have many body tissues and produce wide-
allowing the cycle to start over again. helped our ancestors run from preda- spread effects that prepare the body to
Many other hormones are not tors, but any stressful situation — ar- respond to potential threat. These hor-
regulated by the pituitary gland, guing with your parents, a blind date, a mones stimulate the production and
but are released by specific tissues in looming deadline at work, abdominal release of sugar from storage sites such
response to physiological changes. The cramps, discovering your apartment as the liver, making energy available to

10 The Body in Balance
muscles. They also bind to brain areas (hardening of the arteries), increasing important roles in brain development.
that ramp up attention and learning. the risk of heart attacks. Because the If a pregnant woman suffers from
And they help inhibit nonessential hormones inhibit immune system chronic stress, the elevated stress hor-
functions like growth and immune function, they also reduce resistance to mones can cross the placenta and shift
responses until the crisis ends. infection and inflammation, some- the developmental trajectory of her
It’s easy to imagine how (and why) times pushing the immune system to fetus. Glucocorticoids are transcription
these physiological changes make your attack the body’s own tissues. factors, which can bind to DNA and
body alert and ready for action. But Chronic stress can also have specif- modify which genes will be expressed
when it comes to stress, your body can’t ic negative effects on brain tissue and as proteins. Studies with animal mod-
tell the difference between the danger function. Persistently high levels of els have shown that mothers with high
of facing down a bull elephant and the glucocorticoids inhibit neuron growth blood levels of glucocorticoids during
frustration of being stuck in traffic. inside the hippocampus, impairing the pregnancy often have babies with low-
When stress is chronic, whatever its normal processes of memory forma- er birth weights, developmental delays,
cause, your adrenal glands keep pump- tion and recall. Stress hormones can and more sensitive stress responses
throughout their lives.
Because metabolic stressors such as
starvation induce high glucocorticoid
levels, it’s been suggested that these
hormones might help prepare the fetus
Chronic stress can also have for the environment it will be born
into. Tough, stressful environments
push fetuses to develop stress-sensitive
specific negative effects on brain “thrifty” metabolisms that store fat eas-
ily. Unfortunately, these stress-sensitive
tissue and function. metabolisms increase a person’s risk of
developing chronic metabolic diseases
like obesity or diabetes, especially if they
subsequently grow up in lower-stress
environments with plentiful food.
The effects of stress can even be
ing out epinephrine and glucocorti- also suppress neural pathways that are passed to subsequent generations by
coids. Many animal and human studies normally active in decision-making epigenetic mechanisms. Chronic stress
have shown that long-term exposure to and cognition, and speed the deteri- can change the markers on DNA
these hormones can be detrimental. oration in brain function caused by molecules that indicate which of the
aging. They may worsen the damage genes in a cell are expressed and which
Chronic Stress caused by a stroke. And they can are silenced. Some animal studies
Overexposure to lead to sleep disorders — cortisol is indicate that when changes in markers
glucocorticoids can also an important wakeful signal in occur in cells that develop into eggs or
damage a wide range of physiological the brain, so the high cortisol levels sperm, these changes can be passed on
systems. It can cause muscles to due to chronic stress may delay sleep. and expressed in the animal’s offspring.
atrophy, push the body to store energy Stress-induced insomnia can then start Further research might reveal wheth-
as fat, and keep blood sugar abnormal- a vicious cycle, as the stress of sleep er chronic stress has similar effects
ly high — all of these can worsen the deprivation leads to the release of even in humans, and whether inheriting
symptoms of diabetes. Overexposure more glucocorticoids. silenced or activated genes contributes
to glucocorticoids also contributes to The effects of chronic stress may to family histories of cancer, obesity,
the development of hypertension (high even extend beyond a single indi- cardiovascular, psychiatric, or neurode-
blood pressure) and atherosclerosis vidual, because glucocorticoids play velopmental disease.

CHAPTER
11
Childhood
AUTISM SPECTRUM
DISORDERS
Autism is often considered a
childhood condition, although
Disorders many of its symptoms persist lifelong.

Some people with autism also have
mood and anxiety disorders, seizures,
intellectual disability, attention deficit
hyperactivity disorder (ADHD), and
obsessive-compulsive disorder (OCD).
However, more than 40 percent of
people with autism have normal or
above-average intelligence. With
symptoms that range from mildly to
severely disabling, autism is considered
a spectrum. Autism spectrum disorders
(ASD) are diagnosed based on two
main criteria: impaired social commu-
nication and interaction, and repetitive
behaviors or narrow, obsessive inter-
ests. For example, some people on the
autism spectrum are unable to speak,
while others are socially awkward but
highly articulate. Many adults with an
autism diagnosis think of their autism
as a strength — enabling or motivating
them to develop deep expertise in an
area or a different perspective on the
world — rather than a disorder that
needs to be cured.
Currently, 1 of every 68 American
8-year-olds is estimated to meet the
diagnostic criteria for an autism spec-
trum disorder. The prevalence of ASD
has risen dramatically since the 1970s,
but it is unclear whether changes to
diagnostic criteria and wider recogni-
tion of ASD have contributed to the
increase in diagnoses.
Four to five times more boys
than girls are diagnosed with autism,
although it is not clear whether some
of that pattern is because of underdi-
agnosis of girls. Environmental factors
such as parents having children later in
life, fever and infection during preg-
nancy, and premature birth have been
Brain Facts 71
11 Childhood Disorders
linked to an increased risk of autism and TSC1 or TSC2 (tuberous sclerosis And unlike diabetes, kidney disease, or
in children. A huge number of studies complex 1 and 2), which also code for thyroid disease, there are no biochem-
have found no connection between proteins that help control cell growth ical or other biomarkers of autism.
childhood vaccination and the increase and size. Between 50 to 60 percent of Currently, autism diagnosis is based on
in autism diagnoses. people with fragile X syndrome and behavioral analysis, but efforts are un-
Autism is believed to be at least approximately 40 percent of people derway to use more objective criteria
partially driven by genetics, but how with tuberous sclerosis complex have such as tracking eye movements and
do scientists know that for sure? One ASD. Children with a variant of the functional neuroimaging, which can
low-tech approach uses twin studies: gene NF-1 develop tumors in child- even be done in infants.
If one of a pair of identical twins hood (neurofibromatosis) and a 2011 How early can autism be detect-
receives an autism diagnosis, the other study found that nearly 10 percent ed? Parents often notice develop-
twin has greater than a 50 percent met the criteria for autism. mental issues before their child’s first
chance of also being diagnosed with Intriguingly, these ASD-related birthday, and autism can be reliably
ASD. Children who have an older genes influence a major signaling diagnosed based on behavioral
sibling on the spectrum also have a pathway for regulating cell metabo- characteristics at age 2. Despite these
higher likelihood of being diagnosed lism, growth, and proliferation, the possibilities for early detection, most
with autism — nearly one in five also mTOR pathway. This suggests a very American children aren’t diagnosed
receives a diagnosis of ASD. real potential for treating autism with until they’re about 4½ years old. With
The genetics of autism is very drugs that target the mTOR pathway. evidence mounting that interventions
complicated in most cases, involving
dozens (or more) of genes, leading
to a unique condition in nearly
every person. Recently, however,
The genetics of autism is very

high-throughput genomic analyses
have broadened the pool of potential
genes, revealed their roles in the body,
and suggested possible new therapies.
It appears that many genes, each
complicated in most cases, involving
with a small effect, contribute to the dozens of genes, leading to a unique
inheritance of most ASDs. But such
small effects make these genes hard to condition in nearly every person.
identify in genome-wide association
studies. Scientists are now looking at
the rare variants associated with ASD.
These afflict fewer people with ASD,
but their effects are larger and easier to For example, mouse models with are more effective the earlier they be-
detect. Some of these rare mutations mutations in PTEN show traits simi- gin, researchers are hoping that more
are in single genes whose impairment lar to humans with these gene vari- objective measures will enable earlier
is already known to cause intellectu- ants: altered sociability, anxiety, and diagnoses and interventions.
al disability and social dysfunction. repetitive behaviors. These behaviors Although the molecular caus-
These genes include FMR1 (codes for can be relieved or reversed by drugs es and characteristics of autism are
fragile X mental retardation protein, that inhibit the mTOR pathway. unclear, it appears that the condition
but its non-mutant form is needed Clinical trials of these drugs (rapamy- results from unusual cellular develop-
for normal cognitive development); cin and lovastatin) are underway. ment within the cerebral cortex — a
PTEN (codes for a tumor suppressor Despite this progress, autism brain region that is crucial to mem-
enzyme that regulates cell division, genetics is so complicated that it can’t ory, attention, perception, language,
so cells don’t divide or grow too fast); be used to diagnose the condition. and other functions. Both white

Childhood Disorders 11
and gray matter of the brain show impulsive, and inattentive from time lease dopamine, a chemical messenger
consistent, but subtle, alterations in to time, these symptoms are more involved in rewarding behavior.
people with ASD. Long-term studies extreme and last longer in children ADHD has no cure, but treat-
also have found that a minority of with ADHD. They often struggle to ments include drugs, behavioral
children on the autism spectrum have form strong friendships, and their interventions, or both. Interestingly,
abnormally large brain volumes and grades in school can reflect their ADHD medications include stimu-
faster brain growth. Other toddlers behavior instead of their academic lants such as methylphenidate, as well
with autism have shown unusual ability. Executive functions, such as as newer, non-stimulant drugs. The
development and network inefficien- finishing what they start, remembering drugs are available in long-acting for-
cies at the back of the cerebral cortex. to bring homework back to school, mulations so children do not have to
There is evidence that some atypical and following multistep directions, can interrupt the school day to take their
activity occurs in the cortex of people be especially challenging for those with medication. Determining the right
with ASD from older childhood into ADHD. Young people with ADHD drug and the right dose might require
adulthood, and information might also have lower rates of high school a period of experimentation and sup-
not be integrated in the usual way graduation and a higher risk of suicide. port from a specialist, since dosage is
across distributed brain networks. No objective diagnostic test exists adjusted to how fast a child metaboliz-
At this point, no medications have for ADHD, so diagnosis requires a es the drug, and to minimize the side
been proven to reverse autism. Some comprehensive evaluation, including effects. Nevertheless, most children
people get symptomatic relief from a clinical interview and parent and with ADHD are diagnosed and treated
drugs designed for other uses, such as teacher ratings. Because problems by their pediatricians. Effective behav-
anxiety conditions, and several stud- with attention and hyperactivity can ioral treatments include organizational
ies have reported social benefits from be caused by other conditions such as support, exercise, and meditation.
treatment with oxytocin — a hormone depression, sleep issues, and learning
known to improve social bonding — disorders, careful evaluation is always DOWN SYNDROME
but the findings have been mixed. For needed to determine whether ADHD Down syndrome is named for the
this challenging disorder, behavioral is truly the cause of the symptoms. To English physician who first described
therapies are still the only proven treat- warrant an ADHD diagnosis, atten- it in 1866, but nearly 100 years passed
ments for autism, and early intervention and behavioral problems must be before scientists determined what
tions are the most effective. severe enough that they interfere with caused the condition: possessing an
normal functioning. In addition, the extra copy of all or part of the 21st
ATTENTION DEFICIT behavioral issues must be present in chromosome. People with this syn-
HYPERACTIVITY DISORDER more than one context — not only at drome have three copies of this genetic
Attention deficit hyperactivity home or at school, but in both settings. material, instead of two. In some cases,
disorder (ADHD) is one of the most Although ADHD tends to run in the extra copy, or trisomy, does not
commonly diagnosed childhood families, no well-defined set of genes occur in every cell, producing what’s
conditions. In 2014, approximately is known to be responsible for the known as mosaicism. Currently, about
11 percent of American parents with condition. Environmental risk factors, 250,000 people in the United States
a child between the ages of 4 and 17 such as extreme early adversity, expo- are living with Down syndrome.
reported that their son or daughter sure to lead, and low birthweight, can There is no clear cause of the
had received an ADHD diagnosis. In also be involved. People with ADHD genetic glitch, although maternal age
at least 30 percent of those diagnosed do not demonstrate any obvious brain is a major risk factor for Down syn-
with ADHD, the disorder continues alterations, but research has found that drome. Mothers older than 40 are 8.5
into adulthood. people with ADHD might have dif- times more likely to have a child with
ADHD is usually characterized by ferences in the structure of brain cells Down syndrome than mothers aged
inattentiveness, as well as hyperactivity and in the brain’s ability to remodel 20 to 24. Advanced paternal age has
or impulsive behaviors. Although all itself. Some people with ADHD show also been linked to higher incidence
young children can be hyperactive, unusual activity in brain cells that re- of Down syndrome.

11 Childhood Disorders
Since late 2011, fetuses can be are believed to be a key factor in brain reading skills and fluency can improve,
screened for Down syndrome using the or intellectual differences in Down syn- dyslexia persists lifelong.
mother’s blood. In the past, the risk of drome. Dysfunction in the mitochon- Deciphering printed letters and
test procedures meant that only older dria, the cell’s power plants, might also words and recalling their sounds and
mothers (whose likelihood of having a play a role in development of related meaning involves many areas of the
Down syndrome child was known to disorders that involve energy metabo- brain. Brain imaging studies indicate
be higher) should be screened. Younger lism, such as diabetes and Alzheimer’s. these areas can be less well connected
mothers didn’t know until delivery Scientists have grown stem cells in people with dyslexia. One of these
whether their child would have Down from fetuses with Down syndrome and areas is a region on the left side of the
syndrome. The new blood test, unlike used them to test potential treatments brain called the “word-form area,”
amniocentesis and chorionic villus and confirm which molecular path- which is involved in the recognition of
sampling, poses no risk to the baby, so ways are involved in the condition. In printed letters and words. People with
it can also be used for younger moth- one such laboratory study, researchers dyslexia also show less brain activity in
ers whose chance of having a child took a gene that normally inactivates the left occipitotemporal cortex, which
with Down syndrome is quite small. the second X chromosome in female is considered essential for skilled read-
Children born with Down syn- mammals and spliced it into a stem cell ing. Researchers believe that the brain
drome have distinctive facial features, that had three copies of chromosome differences are present before the read-
including a flattened face and bridge 21. In these cells, the inactivation gene ing and language difficulties become
of the nose, eyes that slant upward, muted the expression of genes on the apparent — although it is possible
and small ears. They usually have small extra chromosome 21, believed to con- that people with dyslexia read less and,
hands and feet, short stature, and poor tribute to Down syndrome. Although therefore, their brains develop less in
muscle tone as well. The intellectual this is a long way from any clinical ap- regions associated with reading. Those
abilities of people with Down syndrome plications, the model is being used to with dyslexia appear to compensate for
are typically low to moderate, although test the changes and cellular problems reduced activity on the left side of the
some graduate from high school and that occur with the tripling of the 21st brain by relying more heavily on the
college, and many successfully hold chromosome, in hopes of eventually right side.
jobs. Other symptoms of Down finding a treatment. Genetic analyses have revealed a
syndrome can include hearing loss and handful of susceptibility genes, with
heart defects, and virtually everyone DYSLEXIA animal models suggesting that these
born with Down will develop early-on- Dyslexia is the most common genes affect the migration of brain
set Alzheimer’s disease, often in their and best-studied of the cells during development, leading to
40s or 50s. Chromosome 21 contains learning disabilities, affecting as many differences in brain circuitry. Dyslexia
the gene that encodes amyloid precur- as 15 to 20 percent of all Americans. runs in families, with roughly half of
sor protein (APP), an Alzheimer’s dis- People with dyslexia have a pro- dyslexics sharing the condition with
ease risk factor, and possessing an extra nounced difficulty with reading a close relative. When one twin is
copy of this gene might cause the early despite having normal intelligence, diagnosed with dyslexia, the second
onset of this fatal disease. Interestingly, education, and motivation. twin is found to have the condition
people with mosaic Down syndrome Symptoms include trouble with 55-70 percent of the time. But the
seem to have milder symptoms and are pronunciation, lack of fluency, diffi- genetics of dyslexia is complex, and
more likely to live past 50. culty retrieving words, poor spelling, likely involves a wide range of genes
There is no real treatment for and hesitancy in speaking. People with and environmental factors.
Down syndrome, nor any clear expla- dyslexia might need more time to Treatment for dyslexia involves
nation of what occurs in the brain. respond orally to a question and might behavioral and educational interven-
Poor connections among nerve cells in read much more slowly than their peers. tion, especially exercises like breaking
the hippocampus, the part of the brain Dyslexia is usually diagnosed in elemen- words down into sounds and linking
involved in memory (and the first brain tary school, when a child is slow to read the sounds to specific letter patterns.
area affected by Alzheimer’s disease), or struggling with reading. Although Some researchers use a child’s ability

Childhood Disorders 11
to rapidly and automatically name and become unaware of what is going spread to become generalized seizures.
things as an early indicator of dyslexia. on around them. The pattern of symp- In some patients with severe epilepsy,
This rapid automatic naming, and the toms and after-seizure brain recordings multiple types of seizure can occur at
ability to recognize and work with the using EEGs are used to distinguish the same time.
sounds of language, are often impaired between different types of epilepsy and Epilepsy has many possible causes
in people with dyslexia. Both skills can determine whether the true cause of and thus is considered a spectrum
be used in preschoolers and kinder- the seizures is epilepsy or a different rather than a single disorder. Causes
gartners to predict their later reading medical condition. include premature birth, brain trauma,
skills. Research suggests that treat- Seizures are classified by where and abnormal development due to
ments targeting phonology, as well as they occur in the brain. General- genetic factors. Attributes of epilepsy
multiple levels of language skills, show ized seizures affect both sides of the patients such as head size, movement
the greatest promise. brain. They include absence or petit disorders, and family history suggest
that genetics is involved.
Seizures can also accompany or
cause intellectual or psychiatric prob-
lems. For example, some seizures may
Epilepsy has many possible causes

suppress the growth of dendrites, leav-
ing the person emotionally unsettled
or less able to learn.
Treatments for epilepsy are direct-
and thus is considered a spectrum ed toward controlling seizures with
rather than a single disorder. medication or diet. For most patients,
a single medication is enough to
control seizures, although a significant
minority cannot get adequate control
from drugs. About half of epilepsy pa-
tients, particularly those with general-
ized epilepsy, can reduce their seizures
EPILEPSY mal seizures, which can cause rapid by eating a ketogenic diet, which relies
If someone has two or more blinking or a few seconds of staring heavily on high-fat, low-carbohydrate
seizures that cannot be explained by a into space, and tonic-clonic or grand foods, although it’s unclear why this
temporary underlying medical condi- mal seizures, which can make some- diet is effective. For severe cases that
tion such as a high fever or low blood one fall, have muscle spasms, cry out, are not relieved by medication, doctors
sugar, their medical diagnosis will be and/or lose consciousness. Focal or might recommend surgery to remove
“epilepsy” — from the Greek words partial seizures are localized to one or inactivate the seizure-initiating part
meaning to “seize,” “attack,” or “take area of the brain. A simple focal sei- of the brain. In the most severe cases,
hold of.” About 1 percent of Ameri- zure can cause twitching or a change if one side of the brain triggers sei-
can children and 1.8 percent of adults in sensation, triggering strange smells zures on the other side, surgeons may
have been diagnosed with this brain or tastes. Complex focal seizures can perform “split-brain surgery,” cutting
disorder. Seizures result from irregular leave a person confused and unable the corpus callosum, a thick band of
activities in brain cells that can last to answer questions or follow direc- white matter that connects the two
five or more minutes at a time. Some tions. A person can also have so-called sides of the brain. Once their seizures
seizures look like staring spells, while secondary generalized seizures, which are controlled, people with epilepsy
others cause people to collapse, shake, begin in one part of the brain but can resume their normal lives.

CHAPTER
12
Psychiatric L
ike many health conditions,
psychiatric disorders can be
caused by multiple factors.
Genes often play a role, with many
Disorders psychiatric disorders tending to run

in families. Yet having a close relative
with anxiety, schizophrenia, depres-
sion, or another psychiatric condition
does not mean that you will develop
the same problem. Many environmen-
tal effects, including life circumstanc-
es, medical conditions, and personal
relationships, also have an influence.
Environmental factors can be negative
— like the death of a loved one, pover-
ty, addiction, or being exposed directly
to violence such as military combat
— or they may be protective. These
so-called resilience factors include a
strong support system of family and
friends, good coping skills, being
physically active, and involvement in a
range of activities.
ANXIETY DISORDERS
AND POST-TRAUMATIC
STRESS DISORDER
Everyone feels anxious at
times, and worrying is a
normal and healthy response to
uncertainty or potential danger. But
unhealthy, uncontrollable anxiety is
the common thread in a variety of
psychiatric disorders: post-traumatic
stress disorder (PTSD), obsessive-com-
pulsive disorder (OCD), and panic
attacks. Collectively, anxiety disorders
are the most common mental disorders
experienced by Americans. They are
more common in women, for reasons
that are not clear but likely include
both sex differences (biological) and
gender differences (psychosocial).
Medications used to treat most
anxiety disorders work by altering
the levels of neurotransmitters that
carry signals between brain regions.
Psychiatric Disorders 12
Selective serotonin reuptake inhibitors and compulsions. One such region, pulses intended to reset abnormal
(SSRIs) raise serotonin levels, which the basal ganglia, connects with the neuronal firing. Scientists are begin-
are known to be deficient in many cortex to help control our ability to ning to explore the use of DBS in the
psychiatric conditions. Benzodiaze- move and think, but it also helps us basal ganglia and several other brain
pines (such as diazepam, or Valium) conduct routine behaviors that we regions to alleviate the symptoms
were once the standard medication call habits. The basal ganglia are also of OCD.
for anxiety because they boost levels involved in the brain’s reward sys-
of the inhibitory neurotransmitter tem, our ability to feel good, and in Panic Disorder
gamma-aminobutyric acid (GABA). learning and memory; these functions Panic disorder is a type of anxiety
GABA acts like a “brake pedal” on are mediated by the neurotransmitters disorder characterized by sudden,
neurons, helping to decrease their dopamine, serotonin, and glutamate, unexpected bouts of intense, irra-
activity, especially in areas of the respectively. Reward systems are often tional fear and frightening physical
brain important in anxiety. However, dysfunctional in people with psychiat- symptoms such as difficulty breath-
because of the risk of dependence, ric disorders, addiction, or both. ing, a racing heart, sweating, and
benzodiazepines are no longer the first Researchers suspect that disrupted dizziness. It is more common than
choice for treatment of anxiety. signaling between the basal ganglia OCD, affecting 2.7 percent of U.S.
and the cortex could set the stage for adults and about the same proportion
Obsessive-Compulsive Disorder ritualistic behaviors. Studies of repetitive of teens. Panic attacks typically last
OCD is a common, chronic con- behaviors in mice have revealed electri- several minutes or sometimes longer.
dition aptly named for its symptoms: cal activity that starts and ends in nerves Because the attacks occur unpredict-
uncontrollable, recurring thoughts that connect these two brain regions. ably, people who experience them
(obsessions) and repeated, ritualistic The ability to manipulate, or “over- often live in fear of having an attack
behaviors (compulsions) to banish, ride,” those circuits may point the way in public or while driving — further
relieve, or compensate for the obses- to breaking the obsession-compulsion increasing their anxiety. About half of
sions. OCD affects about 1 percent of cycle in people with OCD. people with panic disorder also have
U.S. adults, with an average age of 19 About 70 percent of people mood disorders such as depression or
at diagnosis. Obsessions vary widely: A with OCD obtain limited relief with bipolar disorder, as well as other psy-
person may, for example, worry about medication, primarily SSRIs, but at chiatric illnesses like OCD, phobias,
getting sick from a contaminated higher doses than are used for depres- and schizophrenia. Panic disorder is
object, or feel the need to be “perfect” sion therapy. If SSRIs do not work usually treated with psychotherapy,
all the time. Compulsions attempt to to control OCD, other approaches medications, or a combination of
counteract those thoughts behavioral- include medications such as the tricy- these. SSRIs are the primary drugs
ly — for example, by excessive hand clic antidepressant clomipramine and used for panic disorder, although
washing, or constantly checking for neuroleptic (tranquilizing) drugs, both benzodiazepines can be used in an
mistakes or problems such as leaving of which have significant side effects. emergency situation.
appliances on. Another type of OCD Cognitive behavioral therapy, a form
is hoarding, provoked by the fear of of counseling, can also be useful. Deep Post-Traumatic Stress Disorder
losing or forgetting important infor- brain stimulation (DBS) is a thera- PTSD is somewhat unique
mation after discarding something. peutic approach used for people with among psychiatric disorders
People with OCD are burdened by OCD who do not respond to stan- because it has a well-defined cause: a
their obsessive thoughts and, although dard drug or behavioral treatments. harrowing, traumatic event such as
compulsive behaviors can provide DBS was first used about 30 years military combat, a natural disaster, a
relief, they do not bring pleasure. ago to treat movement disorders like terrorist attack, a serious accident, or
Research studies that examine the Parkinson’s disease, but is now being physical or sexual assault as a child or
brain with powerful imaging tools have investigated for other uses. In DBS, adult. PTSD can arise quickly after the
enabled neuroscientists to define the electrodes implanted at specific brain distressing event, but sometimes it can
brain regions involved in obsessions locations emit high-frequency electrical take months to years for symptoms to

12 Psychiatric Disorders
emerge. Symptoms are often severe of PTSD, including changes in brain MOOD DISORDERS
enough to interfere with relationships structure. Many people with PTSD Mood is a vague term describ-
or work. Some people have PTSD for have a smaller hippocampus (the brain ing a person’s general state of
many years, experiencing flashbacks region integral for learning and memo- mind. You can easily recognize some-
and nightmares, intrusive memories of ry) and a smaller prefrontal cortex (the one in a good mood and, likewise, in a
the traumatic event, and hyperarousal part of the brain that helps control not-so-good mood. Your moods
— feeling on edge and/or angry. To thinking, emotions, and behavior). In change frequently with your emotional
compensate, individuals with PTSD contrast, the brain’s emotional center, state, and such changes are normal
try to avoid trigger situations but the amygdala, is apparently overactive when they suit your context and
nonetheless may experience memory
loss, feelings of blame, and decreased
interest in everyday activities. Current-
ly, cognitive behavioral therapy is
Neuroimaging studies have

thought to be the most effective
treatment for PTSD.
Neuroscientists have discov-
ered physiological changes in people
with PTSD. These changes include
begun to reveal the neurobiological
increased heart rate and heightened signatures of PTSD, including changes
electrical sensitivity throughout the
skin and on the face in response to in brain structure.
audio or video triggers of traumatic
scenes like gunfire or other violence.
Simply recalling the initial traumatic
event can also bring on these symp-
toms. Another hallmark of PTSD is in responding to stimuli in people surroundings. Mood disorders, on the
shallow sleep with increased periods of with PTSD. Genes are involved in other hand, are mood changes that
rapid eye movement, which can lead to PTSD susceptibility, but research become longer lasting and indepen-
sleep deprivation over time. The body’s results are not yet conclusive regarding dent of what is going on around you.
general response to stress is maximal in the importance of their role or which The two main mood disorders are
PTSD, with altered levels of hormones genes are involved. What is clear, how- major depression and bipolar disorder.
such as cortisol and norepinephrine, ever, is that genes affecting PTSD risk In recent years, neuroscientists have
the primary fuels in the fight-or-flight also affect the risk for major depres- made major progress in linking genetic
response to danger or fear. Not surpris- sion, generalized anxiety disorder, and and other biological contributors to
ingly, PTSD treatment includes drugs panic disorder — suggesting common mood disorders and to disorders of
that block norepinephrine, such as the biological components of these psychi- cognition, like schizophrenia. Hope-
blood-pressure medication prazosin atric conditions. Neuroimaging studies fully, their findings will lead to better
and beta-blocker drugs like propran- that pinpoint brain regions disrupted treatments for people with more than
olol. Scientists have also detected low in PTSD support the development of one such condition.
levels of other neurotransmitters, such new drugs targeting neural function in
as serotonin, in people with PTSD, those regions. Among these drugs are Major Depression
leading to the use of SSRIs for treat- cannabinoids, glutamate, and oxyto- Diagnosis of major depression is
ment. The neurotransmitter neuro- cin — the latter, sometimes called the based on a set of criteria (at least four
peptide Y also appears to offer some “love” or “happiness” hormone, is re- must be met) that have persisted for at
protection against developing PTSD. leased by both men and women during least two weeks. These criteria include
Neuroimaging studies have begun orgasm and is secreted by mothers feeling empty or sad, loss of appetite,
to reveal the neurobiological signatures during childbirth and breastfeeding. irritability, problems with sleep, and

Psychiatric Disorders 12
changes in appetite or weight. Like areas help manage stress, but can be Bipolar Disorder
anxiety, major depression is a common damaged by excessive stress. When Like most people, you probably
psychiatric disorder that contributes researchers showed negative pictures to have good days and bad days, days
to considerable disability and death depressed individuals and looked for when everything goes well and days
worldwide. Often, depression is ac- brain activation, they noted activity in when the whole world seems against
companied by other diseases. Various parts of the cortex linked to the limbic you. But people with bipolar disorder
medical and psychiatric conditions system. Even though the burst of activ- (formerly called manic-depressive
(for example, diabetes, cancer, heart ity soon died down, individuals who illness) experience very intense mood
disease, and addiction) are common showed greater activation were more changes. Their moods swing between
in people who are depressed, and de- likely to have worse depression 18 extreme highs and severe lows, each
pression can make the other problems months later. Such imaging techniques lasting anywhere from a few hours
worse. Nearly 7 percent of American may help identify individuals at risk to several months. High, or manic,
adults — about 16 million people — for relapse. episodes involve boundless energy,
have experienced at least one major Identifying the underlying bio- racing thoughts, and insomnia; they
depressive episode in the past year, and logical features of depression will help may also involve substance abuse
7 out of 10 of these are likely to be in the development of personalized and harmful behaviors like risky sex
female. This striking sex imbalance is therapy. Currently, approved antide- or other unsafe activities. During
not thoroughly understood, but is an pressant medications raise the levels low, or depressive, episodes, people
area of active research. of norepinephrine, serotonin, and do- with bipolar disorder feel very sad
Several factors combine to cause pamine in nerve cell synapses. Among and hopeless, worried, and some-
depression: genes, biological risk the most widely used medications are times suicidal. Some individuals with
factors, environmental triggers, and SSRIs, which block serotonin re- bipolar disorder are hypomanic; they
psychological influences. Many people uptake and are also used to treat other are highly productive, feel great, and
develop depression in response to the psychiatric conditions. These mole- function better than normal. These
stress of a difficult life experience or a cules work by reshaping synapses, and changes may be outwardly subtle —
disabling medical problem such as can- usually require a few weeks to take only noticed by a friend or family
cer or chronic pain. Inside the brain, effect. Cognitive behavioral therapy, member — but can be a clue to more
depression appears to disrupt the often in combination with medica- intense developing mania.
hypothalamus. This region secretes a tions, is also effective in people with Bipolar disorder is difficult to di-
hormone that, via the pituitary gland, depression. This type of counseling agnose. No specific tests, other than a
tells the adrenal cortex to produce works to change thought patterns and set of symptoms medical professionals
more of the stress hormone cortisol. reroute negative, dysfunctional think- use, differentiate it from other psy-
The monoamine neurotransmitter ing. Treating people with depression chiatric disorders such as depression,
systems, which include dopamine and can be challenging, as medications psychosis, or schizophrenia. Research-
serotonin, are also disrupted. Some affect individuals differently. Some- ers don’t understand what causes
cases of depression — typically those times, two or three tries are needed to bipolar disorder, although many
evoked by a stressful incident, situa- find an effective treatment plan. individuals have a family history of
tion, or short-term illness — respond Unfortunately, for some people a mood disorder or psychotic illness.
to treatment, and symptoms go away. with depression, neither medication Some people with depression may
In many cases, though, depression nor psychotherapy works. Research- be at higher risk for bipolar disorder
becomes a chronic condition and de- ers are actively investigating other if a relative is bipolar or has another
pressive symptoms persist without any approaches to treating depression, psychiatric illness like schizophre-
outside influence. such as deep brain stimulation (DBS). nia or autism. Studies analyzing the
As was also observed in people Some promising studies have found genomes of thousands of people with
with PTSD, people with depression that DBS can relieve intense depressive diseases like bipolar disorder have
tend to have a smaller hippocampus episodes that were resistant to other identified genetic changes that appear
and prefrontal cortex. These two brain forms of treatment. to be involved, but more research is

12 Psychiatric Disorders
schizophrenia. Since then, more than

20 similar antipsychotic drugs have
been developed. Most of these drugs
work by damping the dopamine
response, which is thought to drive
schizophrenia’s “positive” symptoms.
For that reason, these medications may
cause tremors and other movement-re-
lated side effects resembling Parkinson’s
disease, which involves low dopamine
activity. The most recently developed
drugs also suppress some serotonergic
Kim, et al. PLoS One, 2010.

activity, which seems to help with the
negative symptoms of schizophrenia.
Scientists have known for many
years, through studying twins and ex-
tended families in which schizophre-
Brain imaging can reveal how the brains of individuals with schizophrenia function differently.
In this image, the areas shown in orange were found to be less active in people with schizo-
nia is common, that this condition is
phrenia compared to healthy controls. highly influenced by heredity. Only
recently, however, with the emergence
needed to understand how and why behavior. People with schizophrenia of powerful tools that scan massive
these DNA misspellings cause serious appear to have lost touch with reality. amounts of DNA information, have
brain dysfunction. They experience “positive” symptoms scientists identified more than 100
Bipolar disorder is notoriously such as hallucinations, delusions, and common genetic misspellings and at
hard to treat. Psychiatrists typically confused thinking, and “negative” least 11 rare ones in the DNA of people
prescribe separate drugs to lessen the ones, including an inability to expe- with schizophrenia. Current research is
highs and stabilize the lows. Medi- rience pleasure and a severe lack of focused on learning more about these
cations such as anti-epilepsy drugs, motivation. Like many psychiatric genes, which affect nerve cell growth
lithium, or so-called atypical antipsy- disorders that first emerge when the as well as development, learning, and
chotics are used for manic periods, human brain matures in the late teens memory. Genes having a proven rela-
and antidepressants or cognitive and early 20s, schizophrenia usually tionship to schizophrenia are potential
behavioral therapy during depressed appears between ages 15 and 25. This targets for new medications.
periods. Most treatments have signif- time period corresponds to develop- Recently, research has uncovered a
icant side effects and, unfortunately, ment of the brain’s prefrontal cortex. new and unusual perspective for think-
up to one-third of people with bipolar Although no cure exists for schizo- ing about schizophrenia therapies. Pre-
disorder do not respond to treatment phrenia and many symptoms do not vious studies had noted that nearly 90
at all, creating enormous hardship for respond to treatment, some people percent of people with schizophrenia
the affected individuals as well as their can pursue personal and professional smoke cigarettes, possibly to provide
family and friends. life goals with the help of medications, relief for their symptoms. Research-
behavioral therapy, or a combination ers have learned that nicotine seems
DISORDERS OF COGNITION of these. Chlorpromazine, the first to relax rigid nerve-cell shape and
Schizophrenia antipsychotic drug, was developed in function in areas of the brain affected
Schizophrenia is a lifelong, the 1950s as an anesthetic for surgery by schizophrenia. Thus, drugs contain-
severe psychiatric disorder that seri- but was soon employed to calm people ing nicotine may prove to be useful as
ously disturbs thinking, emotion, and with psychiatric disorders including future treatments for schizophrenia.

CHAPTER
13
Addiction D
rug abuse has been much
in the news recently, with
particular focus on the over-
prescription and subsequent abuse
of opioids. All too often, this abuse
results in overdose and even death. In
a 6-day period in late August 2017,
one city (Cincinnati, Ohio) reported
that 174 overdose cases flooded their
hospital emergency rooms. The city
is suing the pharmaceutical indus-
try, as are counties in West Virginia,
California, and New York. Addiction
afflicts people around the world, of-
ten with chilling consequences. The
National Institute on Drug Abuse
estimates that the United States
spends $700 billion each year on ad-
diction-associated treatments, crimes,
and lost productivity.
Addiction is a chronic brain disor-
der that affects the body through phys-
ical and psychological dependence.
Intentional, regular use of substances
like opioids, alcohol, tobacco, or other
drugs becomes an addiction when a
person can no longer control his or
her use despite negative consequenc-
es such as loss of control and harm
to themselves or others. One factor
fueling addiction is tolerance — when
a person’s body becomes “used to” a
drug and requires more of it to expe-
rience the same effect. Another facet
of addiction is withdrawal, when lack
of a drug causes the body to react with
unpleasant or life-threatening physi-
cal symptoms. These may range from
moderate headaches or muscle pain to
severe tremors or seizures.
A combination of positive factors
(pleasurable feelings) and negative ones
(avoiding withdrawal) helps to create
an addiction. Cues or triggers, such as
being in a place associated with drug
or alcohol intake or being around oth-
er drug or alcohol users, also provoke
Brain Facts 81
13 Addiction
drug-taking behavior. It is important internal risk factors, such as certain social environment has a significant
to realize, though, that drug use does genes, and external risk factors, such influence on drug-taking behavior
not always lead to addiction. Addic- as stress and a person’s social envi- during childhood and adolescence, the
tion is complex, and many researchers ronment. Often, a person’s social influence of hereditary factors is stron-
are working to understand the various environment both contributes to ger in later stages of addiction, which
interacting influences. addictive behavior and is shaped by usually occur in adults.
Almost all abused drugs produce
pleasure by activating a specific circuit
of neurons, the brain’s reward sys-
tem, which is controlled mainly by
Much remains to be learned about

the neurotransmitter dopamine. This
brain region, called the limbic system,
drives healthy behaviors such as eating
and socializing, but it is also activated
by drugs of abuse. The limbic system
addiction’s causes, but researchers are
helps people experience emotion,
which somewhat explains the mood-
intrigued to find common genetic links
altering properties of many drugs. In
addition, the brain’s reward system
in many different types of addictions.
generates habits and learned behaviors:
When a reward (a delicious food or a
high-inducing drug) generates feelings
of pleasure, we learn to repeat the addictive behavior, creating a cycle OPIOIDS
actions that led to that reward. that is difficult to break. Dating back to prehistoric times,
Studies that track twins, and other humans have consumed opioids by
Mimics and Imposters closely related individuals with and extracting opium (also known as
Drugs of abuse act as without addictions, conclude that morphine) from the juice of poppy
imposters that invade about 50 percent of addiction can flowers. The drug heroin is an opioid
our nervous system, mimicking the be traced to genetic factors. Much that is made (illegally) by drying
messages of naturally occurring remains to be learned about addiction’s morphine, adding various chemicals,
neurotransmitters in our brain circuits. causes, but researchers are intrigued to and then heating it until it evapo-
While some drugs copy the actions of find common genetic links in many rates and becomes a powder. When
neurotransmitters, others can block different types of addictions — those injected into a vein, heroin reaches
neurotransmitter action, and still involving a host of illicit drugs, mari- the brain in 15 to 20 seconds. Once
others alter the way neurotransmitters juana, and legal drugs such as alcohol, there, it is quickly converted back
are released or inactivated. Ultimately, tobacco, and even caffeine. Generally, to morphine, which binds to opioid
in all cases of addiction, drug use the genes linked to addiction fall into receptors, switching on the brain’s
changes the brain’s reward system and one of two categories. Some of these reward system and flooding synapses
other regions involved in judgment genes affect how brain circuits respond with pleasure-inducing dopamine.
and decision-making, contributing to to drugs; others influence the way the The result is a brief rush of intense
addictive symptoms and behaviors. body metabolizes drugs, which then euphoria, followed by a few hours in
Who is susceptible to becoming affects how quickly drugs enter and a state of relaxed contentment.
addicted? A precise answer to this leave the body. Other biological factors Opioids’ effects vary in strength,
question is still elusive, but we now important in addiction are gender toxicity, safety, and how quickly
know a great deal about vulnerabil- and age: Females and males differ in they act. But why do our brains have
ity. As with most health conditions, their risk of addiction as well as their opioid receptors? Our pituitary gland
vulnerability to addiction involves response to treatment. Also, while produces natural versions of opioids

Addiction 13
called endorphins, which help control Treatment NICOTINE

motivation, emotion, food intake, The most effective treatment Nicotine is the addictive substance
and our response to pain. Laborato- for opioid overdose is an in tobacco. Within 10 seconds of
ries produce synthetic opioids, which antidote-like approach using synthet- smoking a cigarette, nicotine arrives
include heroin as well as prescription ic drugs that block opioid receptors. in the brain (as does any other drug
pain medicines like codeine, oxyco- The “antidote,” naloxone, binds to that is smoked). There it attaches to
done (oxycontin), and fentanyl. Much opioid receptors — without produc- proteins on nerve cells called nicotin-
more powerful than other opioids, ing a biological effect — and pre- ic acetylcholine receptors, triggering
fentanyl is used by doctors to treat vents an opioid from binding. If release of many neurotransmitters. It
severe pain. However, illegally made given quickly enough, it can actually also releases neurotransmitters outside
and distributed versions are sold on reverse a potential overdose caused the brain like adrenaline, a stimulant
the black market and can be extreme- by heroin or prescribed painkillers. that raises a person’s blood pressure
ly dangerous. Opioids have many Naloxone can also be used in preven- and quickens their heart rate. In the
medically important uses — suppress- tion, to limit cravings in people brain, it creates a buzz of pleasure and
ing a cough, stopping diarrhea, and highly motivated to quit. Doctors energy — due to release of dopamine
relieving pain — but, in excess, they sometimes prescribe naloxone to a — followed by a calming sensation
can cause breathing to stop, the usual family member of someone at risk of and a rapid boost in attention and
cause of death in an overdose. opioid overdose so they can adminis- memory. The latter finding has led
Over the past two decades, the ter it, and many first responders to ongoing tests of non-addictive
number of overdose deaths involving across the country are taught how to nicotine-like substances as possible
opioids (both prescription opioids administer naloxone in cases of treatments for cognitive disorders such
and heroin) has quadrupled. Near- overdose emergencies. as schizophrenia, attention-deficit
ly 100 Americans, from every walk Drug-based treatment for hyperactivity disorder (ADHD), and
of life, die from opioid overdoses overdoses can save lives, but other Alzheimer’s disease.
each day. As mentioned above, this strategies are needed to treat opioid Tobacco is the leading cause of
opioid-addiction epidemic appears addiction itself and prevent future preventable deaths in the United States,
to stem directly from increased use crises with these highly addictive accounting for approximately 90 per-
of legally prescribed opioid medica- substances. Two other drugs, meth- cent of lung-cancer deaths, 60 percent
tions that began in the mid-1980s to adone and buprenorphine, stimu- of lung-disease deaths, and 30 percent
treat chronic pain. In fact, about 80 late opioid receptors, but produce of deaths from heart disease. Despite
percent of current heroin users say a limited high. They also reduce the well-known health risks of tobac-
their opioid use began with prescrip- withdrawal symptoms from other co use, however, about 20 percent of
tion pain medications; once hooked, opioids; both drugs have milder Americans still smoke. Nicotine itself
they found heroin to be cheaper and withdrawal symptoms of their own. does not cause cancer, but of the thou-
easier to get than the prescription Researchers have found that these sands of chemicals in tobacco, about
medications. Tragically, street heroin therapies can help deter a person 70 are known to be carcinogenic. How-
can be mixed with other dangerous from seeking heroin or other abused ever, nicotine is responsible for other
substances, including high concentra- opioids. Of the two, buprenor- health risks of smoking, including heart
tions of fentanyl that can be imme- phine is safer because its effect is disease and stroke. Like many other
diately fatal. Another contributor to weaker than methadone, and it can addictive substances, nicotine generates
this epidemic was the 1995 intro- be prescribed in an office setting. tolerance; over time, more and more
duction of a long-lasting version of Psychosocial approaches, including nicotine is required to obtain the same
oxycontin. Researchers now believe cognitive behavioral therapy and be- effect. Also like other drugs of abuse,
that, in medical as well as nonmedi- havioral change focused on positive nicotine activates dopamine-producing
cal users, addiction rather than abuse reinforcement, can also be combined reward pathways that induce feelings of
is the main driver of the opioid-over- with drug treatments to treat pleasure and affect motivation, creating
dose epidemic. opioid addiction. the urge to use more.

13 Addiction
Treatment impacts such as drunken driving, region important for movement and
Nicotine is so highly addictive sexual assault, and domestic violence, balance. They also suffer from mem-
that, even though most a primary chronic health problem is ory loss due to the degeneration of
smokers want to quit, few succeed. For associated with alcohol addiction: neurons in the areas of the brain that
some smokers who are highly motivat- cirrhosis, a late-stage of scarring of the govern learning and memory.
ed to quit, some drug treatments liver. The annual U.S. cost of alcohol When does alcohol drinking
(pharmacotherapy) can help. Nicotine abuse and addiction is estimated at become alcohol addiction? Federal
packaged into gum, skin patches, $250 billion. surveys have found that nearly 9 in 10
lozenges, nasal sprays, or inhalers can Ethanol, the addictive ingredient Americans have drunk alcohol at some
sidestep the use of cigarettes or in alcoholic drinks, has tricky effects point in their lives, and an estimated
chewing tobacco. Nicotine replace- on our bodies. Ethanol is water-soluble 15 million have an alcohol use disor-
ment products provide users with so it easily enters the bloodstream and der, which might develop into addic-
lower overall nicotine levels than they quickly travels to the brain. With just tion. As is true of addictions overall,
get with tobacco use, totally eliminate a drink or two, ethanol acts as a stimu- about half the risk of alcohol addiction
exposure to smoke and its deadly lant. At higher blood levels, however, it is thought to be linked to genetics.
contents, and relieve withdrawal acts as a depressant, causing intoxica- Yet, given that not all people who
symptoms. Buprenorphine, used to tion, sleepiness, and even “blackouts,” choose to drink become addicted to
treat opioid addiction, can also help or short-term memory loss. alcohol, it is clear that both genetic and
smokers quit by simulating nicotine’s Ethanol targets gamma- environmental factors contribute to
effect on dopamine. aminobutyric acid (GABA) receptors, alcoholism. Currently, no single factor
One of the newest treatments which drive the brain’s inhibitory or combination of factors can predict
for nicotine addiction is varenicline, system. In this capacity, ethanol calms the risk of developing an alcohol use
approved by the U.S. Food and Drug anxiety, weakens muscles, and delays disorder, although having a parent or
Administration (FDA) in 2006 for to- reaction time. Ethanol also blocks the grandparent with an alcohol use disor-
bacco-cessation treatments. Varenicline N-methyl-D-aspartate (NMDA) type der is a good predictor. For this reason,
is a nicotine mimic that attaches to a of glutamate receptors, which alter neuroscientists often study genetic
special type of nicotinic acetylcholine mood and impair memory, both com- and environmental factors separately,
receptor — one that is thought to be mon features of intoxication. designing some experiments to under-
responsible for conveying nicotine’s Finally, ethanol can stimulate the stand drinking behavior and others to
addictive properties. Doctors consider brain’s pain-relief circuits, fueled by investigate general issues related to mo-
varenicline the best single-drug option natural opioid molecules. This accounts tivation. Researchers often use animal
for nicotine addiction, and it is even in part for ethanol’s feel-good effects in models in these types of studies.
more effective when combined with many people. It is also a diuretic — a
counseling and behavioral therapy. substance that pulls water from body Treatments
For example, smokers are twice as tissues and can cause dehydration. Most people with a problem
likely to quit if the advice comes from Binge drinking — excessive alcohol with alcohol use can benefit
their medical provider. Other useful consumption in a short period of time from some form of treatment before
resources are motivational tools such as — slows heart rate and causes breath- their use becomes a dangerous addic-
cessation hotlines, websites, and social ing difficulties — usually the underly- tion. Treatments include behavioral
media that promote tobacco-free living. ing cause of death in alcohol overdose. therapy such as individual counseling,
Chronic, heavy ethanol use can group therapy, and support groups.
ALCOHOL also change brain structure. People Some medications (disulfiram,
Alcohol, although legal like tobac- with alcohol use disorder (former- naltrexone, and acamprosate) are
co, is also addictive. Together, alcohol ly called alcoholism) can have an used to treat alcohol addiction, and
abuse and alcohol addiction are a se- unsteady gait, tremors, and slurred researchers can now use genetic
rious and costly national health issue. speech; these symptoms result from testing to try to optimize therapy
Aside from secondary behavioral damage to the cerebellum, a brain for individual drinkers.

Addiction 13
heavy marijuana use seems to increase

vulnerability to drug use in susceptible
people, through physical changes in
the brain circuits of reward systems. In
some users, long-term marijuana use
has been linked to schizophrenia.
Our brains make a natural form of
THC called anandamide, which acts
through cannabinoid receptors in the
body that help coordinate movement.
This may explain why people’s driving
is impaired after smoking marijuana.
The hippocampus, involved in mem-
ory and learning, also contains many
THC receptors, possibly explaining
the effects of marijuana on short-term
memory. While relatively little research
Wheeler, et al. Journal of Neuroscience 2013.

has been conducted on the role and
usefulness of marijuana in treating
medical conditions, some studies sug-
gest that another active compound in
marijuana called cannabidiol, or CBD,
which does not produce a high, can
control epileptic seizures, relieve pain
Studies show that the brains of drug addicts look different than those of people who don’t and inflammation, and possibly even
use drugs. This MRI scan reveals a mouse’s thinning cortex, the part of the brain associated treat mental illness and addictions.
with higher-level functioning, following exposure to cocaine. Researchers found that changes
in brain shape and volume were most pronounced when animals were exposed to cocaine in
Many people with post-traumatic
adolescence, suggesting the impact drug use has on brain development. stress disorder (PTSD) self-medicate
with marijuana to cope with anxi-
MARIJUANA increased documented recreational use ety, stress, and insomnia, and a few
Also known as weed or pot, of marijuana in the United States. research studies appear to validate
marijuana comes from the dried Marijuana is not harmless. Neuro- this strategy. These studies show that
leaves, flowers, stems, and seeds of the scientists have discovered that regular marijuana might reduce anxiety, im-
Cannabis plant. The plant contains marijuana use is linked to abnormal prove sleep, and erase trauma-related
the mind-altering chemical tetra- neurobiology in brain regions related memories in people with PTSD, but
hydrocannabinol, or THC, which to reward, cravings, and thought con- it is unknown whether this is due to
distorts perception and alters a person’s trol — all are key players in addiction. CBD, THC, or some other ingredient.
sense of time, space, and self. With- Marijuana use during the teen years More research is needed to explore
in minutes of smoking a marijuana can have long-lasting effects on think- these findings. Similarly, marijuana
“joint,” THC travels from the lungs ing, memory, and learning. Although has been widely regarded as a treat-
to the blood and then into the brain. cannabis-use disorders have been less ment for reducing nausea associated
Eating foods containing THC can also studied than other addictions, some with chemotherapy. However, 2017
create a high, usually within an hour known harms include higher stress lev- information from the National Cancer
of ingestion. Although the federal gov- els due to craving and withdrawal, in- Institute (NCI) says there is currently
ernment deems marijuana illegal, in ability to think clearly, missing school too little evidence to recommend using
recent years several states have passed or work, and risky behaviors while cannabis to treat this side effect of
laws legalizing it. This has substantially intoxicated. As with other addictions, cancer therapy.

13 Addiction
PSYCHOSTIMULANTS
Psychostimulants are chemicals
that excite the brain. They give a
temporary boost to physical and/or
mental function, earning some the
nickname “speed.” One very common
psychostimulant is caffeine, and an-
other is nicotine. While both are legal
and commercially available, nicotine
is highly addictive and can create sec-
ondary problems as the main ingre-
dient in cancer-causing cigarettes and
chewing tobacco.
Other psychostimulants are in
commonly prescribed medications that
NIH.
are sometimes abused recreationally. Methamphetamine abuse can reduce the number of dopamine receptors in the brain,
For example, doctors prescribe am- disrupting mental functions.
phetamine (Adderall) and methylphe-
nidate (Ritalin or Concerta) to treat In the brain, psychostimulants stimulants act in the prefrontal cortex
ADHD and the sleeping disorder nar- work by flooding the brain’s reward to promote arousal and quicken our
colepsy, but these drugs have migrated system with dopamine, the “usual thinking. Studies show that low doses
to the black market and are widely suspect” in most addictions and many of psychostimulants (much less than
sold illegally. Amphetamines, includ- psychiatric disorders. Most psycho- taken in drug abuse) actually improve
ing methylphenidate, are frequently stimulants act and wear off quickly, the brain’s executive function (as in
abused by high school and college stu- leading to a quick high and then an some ADHD treatments), helping
dents. One study determined that, by unpleasant “crash” that encourages with impulse and emotional control,
their senior year, two-thirds of college more use and can be overwhelming, planning and organizing, and pro-
students had been offered prescription both physically and mentally. Meth is ductivity. Such low doses do not lead
stimulants and one-third had used especially addictive, entering the brain to tolerance and addiction, but high
them non-medically to increase focus very quickly and staying there longer doses can impair brain function.
and enhance concentration. than other psychostimulants. People
Illegal psychostimulants that are who continue using psychostimulants Treatments
made in makeshift drug labs and sold develop a tolerance, needing more and Currently the best treatments
on the street include cocaine and more to get high. Over time, these for psychostimulant addiction
methamphetamine, or “meth.” Abusers drugs damage the body’s ability to are cognitive-behavioral therapy and
sometimes smoke these — in particular, release normal amounts of dopamine, motivational incentives, both of which
cocaine (crack) and crystal metham- causing a range of health problems, help steer users away from situations
phetamine (crystal meth) — produc- starting with a lack of drive to engage that trigger drug use. So far, no
ing a rush of euphoria and feelings of in activities that were once pleasurable. effective drugs have been approved for
power and self-confidence. Typically, Neuroscientists are working hard cocaine or meth addiction. However,
the effects are short-lived, prompting to figure out how to prevent and treat now that scientists better understand
repeated use and physical harm to var- addiction to psychostimulants. In the how psychostimulants work in the
ious organs, including the heart. Meth, course of their work, they have learned brain, they are pursuing treatment
in particular, is quite destructive to the a great deal about the brain’s normal strategies that target many neurotrans-
brain itself, as it generates harmful sub- function in motivated behavior. For mitters separately to quell cravings and
stances called free radicals that destroy example, in addition to increasing do- withdrawal symptoms. The neurotrans-
dopamine neurons. pamine in the reward system, psycho- mitter systems include serotonin,

Addiction 13
glutamate, and GABA. Still-experimen- surroundings. Examples of club drugs pressants, and mimic benzodiazepines
tal meth treatments focus on entirely include 3,4-methylenedioxy-metham- like Valium. They are also known as
new targets, such as the brain’s immune phetamine (also known as MDMA, “date-rape” drugs, as people have used
cells (microglia) and oxytocin — the Ecstasy, or Molly), rohypnol (“roofies”), them to facilitate sexual assault by
latter is sometimes called the “love” or GHB (gamma hydroxy-butyrate), and slipping pills into drinks, sedating and
“happiness” hormone because men and ketamine. Designer and club drugs can incapacitating unsuspecting victims.
women release it during orgasm and be stimulants — such as Ecstasy — or Ketamine, called “Special K,” is also
mothers secrete it during childbirth depressants like rohypnol, GHB, a depressant that is legally used as
and breastfeeding. and ketamine. a veterinary anesthetic. When used
Ecstasy is a widely used recreational recreationally, ketamine takes effect
DESIGNER DRUGS drug with similarities to both the stimu- within about 10 minutes, putting
AND CLUB DRUGS lant amphetamine and the hallucinogen users in a trance-like state. Its halluci-
Designer drugs such as “bath salts” mescaline, which occurs naturally in nogenic effects last one or two hours.
and “spice” (synthetic marijuana) are the peyote cactus and has effects similar Recently, scientists have found a totally
synthetic legal substances with psy- to lysergic acid diethylamide (LSD). unexpected use for ketamine: treating
choactive effects. They look like illicit When swallowed, Ecstasy works within depression. Ketamine alters signaling
drugs but can often be bought legally 30 to 45 minutes, and its effects last for of the neurotransmitter glutamate, a
because the people who make them several hours. It initially boosts levels of non-traditional target for antidepres-
continually tweak their chemical struc- neurotransmitters, especially serotonin, sant medications. Perhaps most inter-
tures to evade drug laws. We now know then temporarily depletes their levels in esting are its very rapid effects, which
that these drugs can cause serious, per- the synapses. Chronic Ecstasy use leads occur within minutes to hours instead
manent damage in many brain regions. to long-term changes in areas of the of the weeks required for other current
Like designer drugs, club drugs are also brain critical for thought, memory, and antidepressant treatments. For this rea-
synthetic psychoactive substances that pleasure. Researchers think this harm is son, neuroscientists consider ketamine
look like legal drugs and are named for a result of long-term damage a potential breakthrough, especially in
their use by youth at dance parties and to serotonin circuits. people for whom no other treatments
all-night raves in crowded, high-energy Rohypnol and GHB are both de- have been effective.

CHAPTER
14
Injury & H
umankind has always sought
ways to treat illness, injury,
and pain. For example, the
first known brain surgeries occurred
Illness about 6,000 years ago in Asia Minor.

Also, archaeologists have found skulls
of ancient Incas of Peru with small
pieces of skull carefully removed (a
process called trepanation) to treat
head wounds, or possibly to cure
epilepsy or infections. The earliest of
these Incan skulls did not show any
healing, indicating that the patients
soon died. But by the 1400s, about 90
percent of the ancient skulls discovered
showed bone regrowth.
How did those patients survive
and how did they deal with the pain?
It is likely that herbs like tobacco and
coca leaves, and corn beer might have
been consumed to provide some relief.
As you learn about brain tumors, head
trauma, pain management, and other
problems caused by disease processes,
remember that neuroscience seeks to
understand the roots of these issues.
Such insights will ultimately advance
the medical field, enabling more effec-
tive treatments and therapies for the
future.
BRAIN TUMORS
Each year, more than 79,000 peo-
ple in the United States are likely to be
diagnosed with a tumor that originates
in their brain — a primary brain
tumor. An estimated 26,000 of these
tumors will be malignant (cancerous),
and 53,000 will be benign (noncancer-
ous). In addition, more than 200,000
people will be diagnosed with brain
tumors that develop when cancer cells
from other parts of the body travel
through the bloodstream to the brain.
Called metastatic brain tumors, these
cancers typically spread from tumors of
the lung, breast, skin, colon, or kidney.
Injury & Illness 14
Regardless of its origin, a tumor, or

any space-occupying lesion in the
brain, can be lethal — thus surgical
removal is required for survival.
Types of brain tumors are named
according to the kind of cell from
which they arise and the brain area
where they develop. For example,
many brain tumors are called glio-
mas — a general term for tumors that
arise from the glial cells that support
and protect neurons in the brain. The
most common form of brain cancer
is a glioblastoma — a proliferation of
immature glial cells. The most com-
mon type of primary brain tumor is a
meningioma: a benign tumor arising
National Cancer Institute.
in the meninges, thin layers of tissue

that cover the brain.
Symptoms of a brain tumor vary
with its location and size and also
differ among people. In some cases, a This brain scan shows a tumor in the brain’s left occipital lobe, seen here in bright blue.
tumor causes general symptoms such Knowing exactly where a tumor is located can help doctors start the proper treatment.
as headache, due mainly to the pres-
sure a tumor exerts on the brain. Or, in which the skull is opened and as cancerous brain tumors, radiation may
a tumor located in a part of the brain much tumor as possible is removed. be administered to surrounding brain
controlling vision can cause difficulties Another type of treatment for some tu- areas to help eliminate any cancer
with sight. In other cases, a tumor can mors uses radiation. For this technique, cells that remain in the brain after
damage healthy tissue as it grows. For called stereotactic radiosurgery, a high surgery. People with cancerous brain
example, as gliomas grow, they release dose of radiation is aimed precisely at tumors can also be given chemother-
toxic amounts of glutamate, which can the tumor. A few radiation treatments apy to prevent growth or regrowth
destroy nerve cells near the tumor and can reduce or eliminate the tumor of their tumors. In the past decade,
cause seizures. while sparing healthy tissue nearby. researchers have developed new ways
Several treatments — including More recently, tumors are treated by to administer chemotherapy that allow
surgery, radiation, targeted treatments, multiple beams of ultrasound focused medication to be delivered directly to
and chemotherapy — can be used precisely to intersect exactly at the the brain (tumor), rather than travel-
alone or in combination to treat brain site of the tumor. These interventions ing through the body before reaching
tumors. The goal of the treatments is can be carried out painlessly in awake the brain. For example, after surgical
to remove or shrink brain tumors to patients inside imaging machines that removal of a brain tumor, small wafers
relieve pressure on the brain, as well visualize the tumor in the brain. containing anticancer drugs can be
as eliminating or reducing symptoms Following conventional surgery, implanted in the space previously
such as seizures and headaches. doctors usually prescribe steroid occupied by the tumor. Over time, the
If a tumor can be accessed with- medications to reduce swelling in the wafers slowly dissolve and release the
out injuring nearby areas of the brain, brain. Reduced swelling helps alleviate chemotherapy drugs to nearby areas.
surgery is usually the first step. Brain symptoms such as seizures, memory Researchers have also been study-
tumors can be removed with conven- problems, or confusion that can occur ing various promising treatments that
tional techniques such as a craniotomy, after brain surgery. In patients with target specific cell mechanisms thought

14 Injury & Illness
to be important to cancer cell growth. prevent mature, specialized cells from (primarily gunshot wounds), and
These targeted treatments zero in on dividing and spreading; cancer cells es- injuries due to participation in sports
genes and other cell mechanisms that cape these regulations. Understanding and recreational activities. Death
fuel cancer cell growth, while sparing the normal processes that allow stem rates among people with spinal cord
healthy tissues and causing less severe cells to mature will allow researchers to injuries are significantly higher during
side effects than those that occur with understand what might be going awry the first year after the injury, especial-
conventional radiation or chemother- in cancer cells. ly people whose injuries cause severe
apy. For example, medications that neurological impairments.
help block formation of blood vessels NEUROLOGICAL TRAUMA Few effective remedies have been
are already being used to treat glioblas- Traumatic brain and spinal cord found to repair damage incurred by
tomas. Blocking tumor blood vessel injuries can lead to significant disabili- head and spinal cord injuries; however,
formation is a key strategy in treating ties and death. In the United States, an new methods have come to light for
glioblastomas, because these tumors estimated 1.7 million people sustain preventing damage that develops after
form strong networks of vessels that traumatic brain injuries (TBI) each the initial injury. In addition, there are
feed tumor growth.
Researchers are also testing ways to
stimulate the ability of the body’s own
immune system to stop tumor growth
Understanding the normal processes

— an approach called immunother-
apy. For example, promising research
is using substances called checkpoint
inhibitors, which interfere with the
signals some tumors send to inhibit
that allow stem cells to mature will allow
the immune system’s ability to block
tumor growth.
researchers to understand what might
Another promising area of research
involves gene therapy. This technolo-
be going awry in cancer cells.
gy identifies the genetic components
that promote tumor growth and then
interferes with their ability to work. Re-
search is currently underway on a num- year. Of those, 275,000 are hospi- ongoing efforts to support better reha-
ber of different gene therapies aimed talized, and about 52,000 will die as bilitation techniques as well as research
at killing tumor cells and suppressing a result of TBI. Falls are the leading into the regeneration and repair of
their growth-promoting genes. cause of all traumatic brain injury, and injured tissue.
Other approaches also under motor vehicle/traffic injury is the lead-
development focus on targeted delivery ing cause of TBI-related death. The Traumatic Brain Injury
of antibodies, toxins, and growth- direct medical costs and indirect costs Widespread use of computer-
inhibiting molecules that can attach of TBI, such as lost productivity, are ized tomography (CT) and magnetic
specifically to tumor cells and interfere estimated to be more than $60 billion resonance imaging (MRI) techniques
with their growth. Researchers are a year in the United States. has afforded opportunities to observe
also exploring the role of stem cells in Each year, about 17,000 people the extent of tissue damage in TBI and
both the development and treatment suffer spinal cord injuries in the Unit- determine its medical management.
of brain tumors. Stem cells are undif- ed States, and an estimated 282,000 Traumatic brain injuries are caused
ferentiated, or unspecialized, cells with people currently live with spinal by bumps, blows, or jolts to the head
the potential to develop into any of cord injuries. Vehicle crashes are the that cause multiple minuscule bleeds
a number of specialized cells, such as leading cause of spinal cord injury, or by penetrating head injuries that
neurons. Normally, regulatory processes followed by falls, acts of violence directly destroy brain tissue. TBI can

Injury & Illness 14
be “mild,” such as concussion — a Severe TBIs can cause bruising on replacing damaged nerve cells, stimulat-
temporary disruption in brain activity the surface or within the brain. The ing the regrowth of axons and targeting
— or “severe.” TBI can cause bruises bruising might cause blood to leak their connections, and retraining nerve
in the brain, massive bleeding inside from vessels and contact brain tissue circuits to restore bodily functions. In
the brain, cuts in the brain tissue, di- directly, which can be toxic to brain addition, scientists constantly search
rect nerve damage, and death of nerve cells. Pressure often increases in the for new methods for rehabilitating
cells. Brain injury can trigger swelling, injured area, compresses the blood patients with SCI and improving their
fever, seizures, and other neurological vessels, and reduces critical blood flow quality of life. Rehabilitation focuses on
impairments. Even mild TBI can cause to the injured tissues. If fluid removal physical therapy to strengthen muscles
damage to neurons, which release and medications fail to decrease pres- and improve mobility. Occupational
pro-inflammatory factors that initiate sure on the brain, part of the skull can therapy focuses on enhancing fine
and sustain an inflammatory response. be drilled open or removed to relieve motor skills, such as the skills needed to
People such as professional foot- pressure on the brain. In extreme write or type. Electrical stimulation is
ball players or boxers, who sustain cases of TBI, bruising in the brain can sometimes used to help restore function
repeated concussions and other brain contribute to development of a seizure to muscles affected by the injury.
trauma, might develop a progres- disorder called post-traumatic epilepsy. Scientists have also discovered that
sive degenerative brain disease called Once a person with a brain injury new nerve cells can be born in an adult
chronic traumatic encephalopathy is stable, the long road to recovery be- brain. However, these new cells do not
(CTE). CTE occurs when repeated gins. Physical and occupational therapy seem to help an injured brain repair
head trauma triggers degeneration of are used to help people regain lost func- itself, so studies are ongoing to deter-
brain tissue; this process includes a tions such as speech and movement. A mine how to jumpstart the pathway
buildup of abnormal proteins, which wide variety of medications can be used that stimulates the birth of new nerve
can begin months, years, or even to treat other symptoms of TBI such cells. Stem cells, some even derived
decades after the last brain trauma. as pain, seizures, muscle spasms, sleep from a patient’s own tissues, might
Symptoms associated with CTE disorders, depression, and anxiety. be able to start a new population of
include memory loss, confusion, cells that are able to produce many
impaired judgment, impulse control Spinal Cord Injury cell types, nerve cells among them.
problems, aggression, depression, and, Like TBI, spinal cord injuries Researchers are also working to under-
eventually, progressive dementia. (SCI) can permanently stand how certain neurochemical and
Most people with mild brain inju- damage nerve cells and cause a wide cellular barriers that prevent regrowth
ries, such as concussions, recover fully range of disabilities — including and repair can be overcome and how
in a short period of time. Yet a study various degrees of paralysis. Methyl- the newly born cells can be induced to
of college ice hockey players who had prednisolone, a steroid drug, is the integrate into the injured circuit.
concussions showed that their brain only treatment for SCI currently
volume had decreased two weeks after approved by the U.S. Food and Drug NEUROLOGICAL
the concussion, a change that lasted at Administration (FDA). This medica- ACQUIRED IMMUNE
least two months. Rest and avoidance tion appears to reduce damage to nerve DEFICIENCE SYNDROME
of physically demanding activities cells and decrease inflammation near In 2015, about 2.1 million people
give the brain time to heal and are key the site of the SCI. If administered worldwide became infected with
aspects of recovery. People who arrive in within eight hours of injury, it can be the human immunodeficiency virus
the emergency department with a severe effective in treating spinal cord injuries (HIV), the virus that causes acquired
head injury are carefully monitored for in some people. immune deficiency syndrome (AIDS).
bleeding or swelling that puts pressure There is no cure for spinal cord Currently, an estimated 37 million
on the brain. Treatments for increased injuries, but scientists are investigating people worldwide live with HIV.
pressure inside the skull include renew ways to repair damaged spinal The vast majority live in eastern and
moving an amount of water fluid from cords. These include protecting surviv- southern Africa, and about 40 percent
injured and inflamed brain tissue. ing nerve cells from further damage, of people living with HIV are unaware

14 Injury & Illness
that they are infected with the virus. HAND. Examination of the brains of central nervous system, including the
From 2008 to 2014, the estimated people who die with AIDS sometimes brain, spinal cord, and optic nerves.
number of new HIV diagnoses in the reveal loss of nerve cells, white matter The target of this attack is the myelin
U.S. fell by 18 percent, possibly due to abnormalities, and damage to cellular sheath, a fatty substance that forms
targeted prevention efforts. structures involved in cell-to-cell com- a protective coating around nerve
Globally, the number of people re- munication. Inflammation and vessel fibers; the nerve fibers themselves can
ceiving treatment for HIV has increased disease can also be present. also be affected. As a result of the
dramatically in recent years, particularly Recently, research has indicated that attack, the damaged myelin and the
in developing countries. In 2015, 17 “cocktails” of three or more antiretrovi- accompanying inflammatory cells
million people living with HIV were ral (ARV) drugs active against HIV can form lesions, patches of scar tissue
receiving life-prolonging antiretroviral reduce the incidence of AIDS dementia. that look like sclerosis.
treatment. In 2010, only 7.5 million These treatments can also reverse brain In MS, the patches of disease
people were receiving this treatment. abnormalities caused by HIV. activity appear in multiple areas of the
Although HIV targets the immune Another neurological problem central nervous system, which is why
system, the nervous system can also be commonly developed by people with the disease is called multiple sclerosis.
affected. More than half of people with HIV is peripheral neuropathy. Periph- Damage to the myelin sheaths and
HIV develop HIV-associated neuro- eral neuropathy involves injury to the nerve fibers interferes with transmis-
cognitive disorders (HAND). HAND nerves of the extremities and causes sion of nerve impulses within the
causes mental problems ranging from discomfort ranging from tingling and brain and spinal cord, as well as their
mild difficulty with concentration, burning to severe pain. HIV is believed communication with other body areas.
memory, coordination, and complex to trigger the injury, and certain ARVs The effects of MS are often compared
decision-making to progressive demen- can cause the neuropathies or make to the loss of insulation around an
tia, called AIDS dementia. Even people them more frequent and serious. More electric wire and damage to the wire
who receive antiretroviral treatments than half of people with advanced itself, interfering with signal transmis-
can develop mild symptoms of HAND. AIDS have neuropathy. sion. Damage can occur in the white
The mechanism behind the Despite remarkable advances in (myelin) and gray (nerve cell bodies,
development of HAND is unclear. new therapies, AIDS cannot be cured, glia, etc.) matter of the brain.
Most scientists speculate that certain and some of its neurological prob- The cause of MS is unknown,
proteins in the virus itself, or proteins lems do not respond to treatment. but there are some hints that a genetic
released by cells infected with HIV, In addition, people living with HIV factor is involved. Siblings of people
cause nerve damage leading to the are particularly vulnerable to certain with MS are 10 to 15 times more like-
disorder. Whatever the mechanism, infections and cancers because the ly to develop MS than people with no
HIV infection appears to be the key virus weakens their immune system. family history of the disease. The risk
player in HAND, because antiretrovi- Fortunately, combination ARVs have is particularly high for an identical
ral treatment may prevent or reverse it greatly reduced the incidence of most twin of someone with MS. Oddly, the
in many people. of these infections, as well as some of disease is as much is five times more
Mild forms of HAND have been the neurological problems associated prevalent in temperate climates, such
reported in about one-third of people with AIDS. as the northern United States and
with HIV infection who have no other northern Europe, than in the tropics.
symptoms. In advanced disease, people MULTIPLE SCLEROSIS Although Caucasians run a higher risk
can develop increasing problems with Multiple sclerosis (MS) is an than other races of developing MS,
concentration and memory as well inflammatory disease of the the prevalence of MS indicates that
as an overall slowing of their mental central nervous system, usually risk is shaped by both genetic and
processes. At the same time, they diagnosed in people between 20 and geographical factors.
might experience leg weakness and 40 years of age. For unknown reasons, Damage to the nervous system
loss of balance. MRI and CT scans the immune system of a person with in people with MS can cause a wide
show brain shrinkage in people with MS launches an attack against its own array of symptoms. The spinal cord,

Injury & Illness 14
number of medications are becoming

available or are under investigation.
Since 2010, six new or revised dis-
ease-modifying therapies have been ap-
proved for use in people with MS. In
addition, several medications can now
help control the inflammation and
immune system attacks in relapsing-re-
mitting MS. Steroid drugs, specifically
glucocorticoids, reduce the inflamma-
tion and might also help shorten acute
attacks. Medications and therapies are
also available to control symptoms
such as muscle stiffness, pain, fatigue,
mood swings, and bladder, bowel, or
sexual dysfunction.
CHRONIC PAIN
Pain can be acute — a short-lived
side effect of injury or disease — or
a chronic condition that persists
for weeks, months, or even years.
For some people, pain is the disease
itself. Pain affects more Americans
than diabetes, heart disease, and
cancer combined, afflicting the lives
At the location of an injury, the body produces prostaglandins, which increase pain sensitiv-
ity. Aspirin blocks the production of prostaglandins, thus preventing pain. Opiate drugs act
of approximately 100 million Amer-
in the brain and spinal cord to block pain signals. icans. Back pain, severe headache or
migraine pain, and facial ache are the
cerebellum, and optic nerve are com- by progressive worsening of symptoms most common culprits. In the US,
monly affected by MS, so problems of- after disease onset; and secondary-pro- the cost of healthcare, disability, and
ten arise in functions controlled by those gressive MS, in which relapsing-re- lost productivity due to pain ranges
areas. Symptoms include numbness, mitting disease has transitioned into from $560 billion to $635 billion
clumsiness, and blurred vision. Other a progressive form of disease that annually. Chronic pain can trigger
symptoms are slurred speech, weakness, worsens over time. a cascade of psychological processes
pain, loss of coordination, uncontrol- Within each category, MS is that lead to changes in perception,
lable tremors, loss of bladder control, further classified as “active” or “not attention, mood, motivation, learn-
memory loss, depression, and fatigue. active.” While the categories refer ing, and memory. Increasing evidence
When a person is diagnosed with to the progression of symptoms, the indicates the value of a combination of
MS, treatment options depend on classification refers to presence (“ac- treatments involving drugs, behavior,
the type of disease that is present. tive”) or absence (“not active”) of new physical therapy, and other modalities
Specialists classify MS as one of three areas of inflammation, seen on MRI to fully manage chronic pain.
categories: relapsing-remitting MS, scans. In some cases, MS is defined
characterized by flare-ups of new or as “stable,” meaning that symptoms Treating Pain
worsening symptoms followed by are stable and no activity appears on Anesthesia is used to prevent pain
complete or partial remission of symp- routine MRI scans. during a wide variety of medical pro-
toms; primary-progressive MS, defined MS has no cure, but an increasing cedures and surgery. Local anesthetics

14 Injury & Illness
work by temporarily blocking pain

receptors. Commonly used anesthet-
ics include procaine (Novocain)
and lidocaine.
Once pain occurs, four main
types of painkillers may be used to
relieve it: aspirin and nonsteroidal
anti-inflammatory drugs (NSAIDs)
such as ibuprofen and naproxen;
opioids (powerful drugs that act di-
rectly on the nervous system) such as
morphine and codeine; antiepileptic
agents such as gabapentin; and anti-
depressants such as amitriptyline.
NSAIDs reduce inflammation
and are effective for postoperative
pain and for pain caused by inflam-
mation such as arthritis. NSAIDs
are also useful for treating the mild
or moderate pain of headaches,
sprains, or toothache. NSAIDs work
by inhibiting substances that trigger
the synthesis of pro-inflammatory
and pain-producing chemicals (such
as prostaglandins). Moderate pain is
often treated by combining a mild
opioid like codeine with aspirin or
another NSAID.
Opioids, often used for severe
pain, work directly in the central A stroke occurs when a blood vessel bringing oxygen and nutrients to the brain bursts or is
nervous system by attaching to recep- clogged by a blood clot. Without blood, cells in the brain start to die within minutes. It can
also cause dangerous molecules called free radicals to escape, which can further damage
tors on nerve cells. These drugs not brain tissue. The effects of a stroke, such as movement or speech problems, depend on
only reduce feelings of pain but also where in the brain the stroke occurs.
produce feelings of euphoria. While
highly effective against pain, opioids Psychological therapies such as the nervous system. Nerve damage
do have many serious side effects, cognitive behavioral therapy and and pain (neuropathy) can be due to
such as slowing a person’s breathing. biofeedback can also be used to stim- chronic high blood sugar levels; vi-
Most importantly, they are highly ad- ulate relaxation and release muscle ruses, such as shingles; phantom limb
dictive. The current opioid epidemic tension, thereby helping reduce the pain; or post-stroke pain.
in the United States is caused, in part, effects of chronic pain. Psychological
by the facility to obtain opioid pre- treatments can also help people man- The Body’s Pain Control System
scriptions and poor pain management age changes in mood, perception, Studies of the body’s pain control
of chronic pain. The brain of a person memory, and other psychological fac- system have shown that our bodies
suffering from chronic pain under- tors often affected by chronic pain. produce their own naturally occurring
goes major changes, and the solution Antiepileptic and antidepres- opioids, called endorphins. Scien-
for this complex problem should sant drugs are generally used to treat tists have also identified the recep-
include more than pharmaceuticals. nerve pain that results from injury to tors through which opioids work to

Injury & Illness 14
decrease pain. The finding that opioid STROKE clot-dissolving medications are a
receptors are concentrated in the spi- Each year, nearly 800,000 standard treatment. Tissue plasmino-
nal cord led to the use of injections of people in the United States gen activator (tPA), a clot-dissolving
morphine and other opioids into the suffer a stroke — an interruption in drug approved by the FDA in 1996,
cerebrospinal fluid (CSF) surround- blood flow to the brain due to a helps to break down blood clots and
ing the spinal cord. Remarkably, these ruptured blood vessel or a blood clot. open blocked blood vessels. tPA can
injections enabled profound pain Of these, about 600,000 are first restore circulation before oxygen loss
control without causing paralysis, strokes. Strokes are a leading cause of causes permanent brain damage; given
numbness, or other severe side effects. long-term disability in the United within three hours of a stroke, its use
This technique is commonly used to States, costing about $33 billion each often limits brain damage. In addition,
treat pain after surgery. In addition, year, including the costs of health care surgery to clear clogged arteries and
some patients are given implanted services and medicines to treat stroke, other treatments targeting heart disease
opioid pumps to enable long-term and missed days of work. More than can help prevent strokes. Anticoagu-
treatment of severe chronic pain. 130,000 Americans die of a stroke lant drugs also help by reducing the
Scientists have identified many each year. likelihood of clots forming elsewhere
molecules that are involved in the Risk factors for stroke include in the body and traveling to the brain,
body’s pain response. Developing obesity, physical inactivity, and heart causing a stroke.
drugs that target these molecules disease. Controlling these factors Research is underway to find new
could have great benefit for treating by maintaining a healthful weight, methods for preventing and treating
patients who experience acute or exercising, avoiding excessive alcohol strokes. Some drugs have been shown
chronic pain. intake, and taking medications for to be effective at preventing damage
Advances in brain imaging stroke-related physical problems such to the nervous system, including nerve
techniques have also broadened our as high blood pressure, can reduce the cell death following a stroke. Another
understanding of how the brain risk of having a stroke. There is also a promising research area is the use of
perpetuates chronic pain after a genetic component in stroke risk, es- neural stem cells to improve recovery
painful stimulus has been removed pecially evident if a parent has suffered after a stroke. Preliminary research
and injuries have healed. As a result, a stroke by age 65. To date, several suggests that injection of stem cells
pain researchers are moving toward a candidate genes have been suggested, helps promote recovery, even when
whole-brain approach for their stud- but increased stroke risk is most likely given several days after a stroke.
ies, developing new technologies and due to multiple genetic factors. Administering growth-stimulating
techniques that could lead to better Until recently, treatments for a substances along with the stem cells
diagnosis and more effective treatment stroke did not go far beyond physical might enhance the benefits of the
of chronic pain. or speech therapy. Today, however, stem cell transplant.

CHAPTER
15
Neurodegenerative N eurodegenerative diseases

all involve a progressive
destruction of nerve cells.
Diseases
They more often affect older people,
and are likely to become more com-
mon as life expectancy rises due to
improved medical care — not only in
the in the U.S. but worldwide. From
2015 to 2060, the number of people
65 and older in the U.S. is expected
to jump from 48 million (15 per-
cent of the population) to 98 million
(nearly 25 percent of the population).
As scientists look ahead, the field of
neurodegenerative disease promises to
become increasingly important.
In the past two or three years, arti-
cles in Nature, Scientific American, and
other major science publications have
discussed the intriguing possibility that
many, if not all, neurodegenerative dis-
eases involve misfolded proteins called
prions. You may have heard of prions in
the context of “mad cow disease.” Scien-
tists now wonder if prions also contrib-
ute to more familiar disorders such as
Alzheimer’s disease, Parkinson’s disease,
and amyotrophic lateral sclerosis (ALS,
known as Lou Gehrig’s disease). In the
case of prions, a protein’s normal 3-D
structure has somehow been altered,
so that it no longer functions correctly.
Worse still, the misfolding can cause
proteins to collect in irregular clumps
that can damage cells. Is this really the
cause of neurodegenerative diseases?
Many scientists are asking that question.
As you read this chapter, remember that
there’s still a lot to learn in this field —
and each step toward understanding
normal brain function aids the devel-
opment of prevention or treatment for
thousands of people in the future.
ALZHEIMER’S DISEASE
Alzheimer’s disease is a form
of dementia that is eventually fatal.

Neurodegenerative Diseases 15
Over time, a person’s brain undergoes

irreversible, progressive degeneration
that impairs his or her memory and
reasoning. In the late-onset form of
Alzheimer’s, patients display symp-
toms in their mid-60s or later, with
symptoms becoming more severe
with age. In early-onset forms of the
disease, patients can start to experience
symptoms in their 30s. Fortunately,
early-onset Alzheimer’s occurs in less
than 10 percent of cases of the disease.
Prevalence and Impact

Alzheimer’s is the most common
cause of dementia in older adults. Of
the 47 million people with dementia
worldwide, approximately 60 to 70
percent have Alzheimer’s. The disease
affects 5 to 8 percent of all people
over 65 years of age, 15 to 20 percent
above 75, and 25 to 50 percent of
NIH.
those over 85. It’s estimated that more

Alzheimer’s disease damages and destroys the connections between cells, causing wide-
than 5 million people in the U.S. spread cell death. The damage causes problems with learning, memory, and thinking, and is
suffer from the disease; however, the eventually fatal.
actual number could be as high as 11
million, including many who are now Symptoms of learn new things; problems coping
asymptomatic. Conservative estimates Alzheimer’s Disease with new situations; difficulty getting
are that Alzheimer’s will affect 13.8 Alzheimer’s symptoms are clas- dressed or performing other multistep
million people in the U.S. by 2050. sified by the disease’s progression. tasks; hallucinations, delusions, and
In 2014, Alzheimer’s was the sixth Early stage symptoms include mem- paranoia; and impulsive behavior. In
leading cause of death in the U.S., ory problems (greater than expected the severe stage, patients are completely
accounting for 93,541 deaths. Deaths in healthy people of a similar age), dependent on others for care, as their
rose from 16.5 per 100,000 people in difficulty concentrating or finding body begins shutting down. Their
1999 to 25.4 per 100,000 in 2014, appropriate words, problems judging communication is reduced to groans,
but Alzheimer’s-related deaths are and calculating, and disorientation moans, and grunts; sleeping increases;
believed to be severely underreported. in time or place. Most people are not and they become bedridden. Other
Some patients go undiagnosed, and diagnosed until the mild stage when severe stage symptoms include weight
others have dementia-related condi- symptoms include personality and loss, seizures, difficulty swallowing,
tions (such as aspiration pneumonia) behavior changes, wandering and skin infections, and a lack of bowel
rather than Alzheimer’s listed as their getting lost, repeating questions, losing and bladder control.
primary cause of death. Some estimate and placing objects in odd places,
that the number of Alzheimer’s- taking longer to complete daily tasks, Diagnosing Alzheimer’s
related deaths might be six to seven and having trouble handling money Alzheimer’s dementia is most
times higher than reported. If this is and paying bills. In the moderate stage, commonly diagnosed by a physi-
accurate, it would be the third leading some patients have trouble recogniz- cian asking the patient and a family
cause of death among older Americans. ing family and friends; inability to member or friend about the patient’s

15 Neurodegenerative Diseases
health, medical history, ability to

perform daily activities, and changes
in behavior and personality. Next, the
physician conducts tests on memory,
problem-solving, attention, counting,
and language. Even if mental deficits
are found, including dementia, the
condition still might not be Alzhei-
mer’s. Similar deficits could be due to
other conditions including Lewy body
disease, frontotemporal dementia,
Parkinson’s disease, stroke, a tumor,
sleep disturbances, side effects from
medication, or infection.
Researchers are searching for a
defining biomarker for Alzheimer’s
— a specific indicator that can physi-
cally identify a disease. Two candidate
primary biomarkers are amyloid-beta
(also called beta-amyloid) and tau.
In Alzheimer’s, amyloid-beta forms
extracellular senile plaques, also known
as neuritic plaques. These malformed
clumps contain a fragment of the
Jensfloran.
preliminary protein. In addition,

tau, a type of protein that normally
Amyloid plaques, seen here as dark spots against pink brain tissue, are a hallmark of
stabilizes the cellular skeleton, forms Alzheimer’s disease. Scientists are still investigating whether plaques cause the disease
neurofibrillary tangles inside neurons. or are merely a symptom of it.
Both abnormalities are found in the
brains of people with Alzheimer’s but, disease or other causes of dementia. To a condition known as chronic trau-
at present, no definitive biomarker can date, the FDA has approved the use of matic encephalopathy (CTE) seen in
diagnose the disease in its early stages. three tracers — florbetapir F-18, flute- football players and other athletes who
A diagnosis can only be confirmed by metamol F18, and florbetaben F18 play contact sports. Those with CTE
postmortem examination. — to detect amyloid-beta in the brain. typically show a buildup of tau protein
Some potential diagnostic meth- However, neuritic plaques are also in brain cells; some also have amyloid-
ods for Alzheimer’s include brain present in the brains of people with no beta deposits, but this is less common.
imaging, genetic risk profiling, and dementia or Alzheimer’s, so these scans It appears that patients experience
examining cerebrospinal fluid or are not used for routine evaluation. the first cellular changes associated
blood. Neuroimaging, among the most with Alzheimer’s a decade or more be-
promising areas of research focused on Causes and Pathology fore becoming symptomatic. The neu-
early detection, uses a mildly radio- The causes and mechanisms ronal transport system shows damage
active chemical marker that binds underlying Alzheimer’s disease are not early in Alzheimer’s. Patients produce
to amyloid plaques and shows their fully understood. Most forms are likely fewer neurotransmitters — chemi-
location in PET scans of living people. caused by a combination of heredity, cal molecules that are released from
Starting in 2012, the FDA began ap- environment, and habits. Evidence an axon terminal, travel across gaps
proving the use of molecular imaging has been building that head trauma called synapses, and transmit signals to
tracers to evaluate possible Alzheimer’s is one contributing factor, based on another neuron, organ, or other tissue

type. In Alzheimer’s disease, axons and cortex and the hippocampus, regions C9ORF72 gene has been found in
synapses are damaged and ultimate- responsible for short-term memory people with both early- and late-onset
ly destroyed. Damage to neuronal and for transferring those memories to forms of the disease. This gene codes
transport impairs attention, memory, longer-term memory. for a protein that regulates transpor-
learning, and higher cognitive abilities. Although amyloid-beta and tau tation in the intracellular matrix. The
While the cause is unknown, neuritic accumulations are found in people mutation was already known to play a
plaques and neurofibrillary tangles are with Alzheimer’s, there is no definite major role in ALS and frontotemporal
the two prime suspects. Plaques consist proof that they cause Alzheimer’s. We dementia, but recent studies show that
of amyloid-beta, which is formed from do have evidence that tau and amy- it also disrupts a key mechanism for
malformed clumps of a fragment of loid-beta might interact before clump- DNA repair.
amyloid precursor protein (APP), a fi- ing into their recognized disease forms. The TOMM40 gene, which codes
brous protein often found at neuronal Even before it aggregates, malfunction- for a protein responsible for moving
synapses. In its soluble form, amy- ing tau can damage cellular transpor- proteins into mitochondria, has a
loid-beta can bind strongly to neural tation by blocking the microtubule complex relationship with Alzhei-
receptors, which initiates the erosion tracks. Also, high tau levels can impair mer’s. People with a longer version
of synapses. Evidence indicates that the function of amyloid-beta. of the gene were shown to be either
this soluble form is highly synaptotox- It’s possible that inflammation predisposed or resistant to Alzheimer’s
ic, while the insoluble form (which has and the presence of obesity can trigger — depending on whether a parent
low toxicity) tends to aggregate, and is these protein changes, increasing had the disease. Among those with an
found in much higher concentrations Alzheimer’s incidence and severity. afflicted parent, people with the longer
than the soluble form. Some research Plaques and tangles are known to version of the gene were more apt to
suggests that the highly toxic, soluble negatively interact with microglia, develop dementia than those with the
form would be a better target for non-neural brain cells that act as shorter allele; but among those with no
effective therapies. immune cells for the central nervous afflicted parent, people with a longer
The amyloid hypothesis is cur- system, and astroglia, which offer allele displayed better memory than
rently the dominant theory of how physiological regulation and structural those with a shorter gene allele.
beta amyloid and tau protein interact support in the brain. With the TREM2 gene, loss-of-
to cause Alzheimer’s. This hypothe- function mutations cause a sequence
sis asserts that amyloid-beta starts a Genetics of Alzheimer’s of physiological events associated
sequence of events that ultimately lead Early-onset Alzheimer’s is a rare, with Alzheimer’s disease. This sug-
to Alzheimer’s disease. Amyloid-beta dominantly inherited form of the gests a possible genetic link between
accumulations first appear in the neo- disease. Dominant mutations in three early- and adult-onset variants — the
cortex. Its neurotoxicity might be due genes — APP, PSEN1, and PSEN2 homozygous loss-of-function mutation
to the fact that it exacerbates oxidative — cause early-onset familial Alzhei- is associated with early-onset and the
stress and damages the mitochondria, mer’s disease that starts when people heterozygous variant with adult-
the cell’s primary energy supply unit, are in their 40s and 50s. In late-onset onset. Normally, TREM-2 protein
initiating a cascade of neuronal dys- Alzheimer’s, the ApoE4 variant of the helps regulate removal of cell debris,
function and cell death. The formation Apolipoprotein E (APOE) gene is a clearing amyloid proteins, and sup-
of neuritic plaques induces tau pro- major genetic risk factor but not a pressing inflammation in microglia.
teins to become defective and tangle determining one. The normal protein, Two large programs are current-
into neurotoxic neurofibrillary tangles ApoE, is mainly produced by astroglia ly studying early-onset Alzheimer’s.
(hyperphosphorylated tau protein) or damaged neurons and helps clear The Dominantly Inherited Alzheimer
within neuron cell bodies. (In contrast, soluble amyloid-beta from the brain. Network project is funded by the
normal tau protein stabilizes micro- In most people, Alzheimer’s results U.S. National Institute on Aging with
tubules, which are crucial to axonal from a combination of genetic and en- 10 research centers in Australia, the
transport). Neurofibrillary tangles are vironmental causes. Several genetic as- United Kingdom, and the United
generally first seen in the entorhinal sociations have been noted. A mutant States; and the Alzheimer’s Prevention

Initiative is studying an extended rate for drugs on the road to approv- Parkinson’s disease increased in the
family of 5,000 with the disorder in al. Between 2002 and 2012, just 0.4 U.S. from 8.8 to 11.0 per 100,000
Antioquia, Colombia. percent (1 in 245) of Alzheimer’s drugs for males and from 3.9 to 4.8 per
were approved. Potential drugs have 100,000 for females. For reasons not
Treatments for Alzheimer’s often proved ineffectual because they yet understood, the disease is more
The FDA has now approved don’t target Alzheimer’s early pathology. prevalent in men than in women. Five
five prescription drugs for Online registries may improve the situa- to 10 percent of cases are “early-onset,”
treating Alzheimer’s. While they relieve tion by hastening participant recruit- occurring before age 50. Rarer still,
some symptoms, they do not cure or ment for clinical trials and looking for patients with “juvenile Parkinsonism”
halt the disease. Three of these drugs people at ever-earlier stages of disease may develop symptoms before age 20.
are cholinesterase inhibitors: donepez- progression. Trials are also broadening Estimates of the prevalence, or
il, galantamine, and rivastigmine. their pool of participants to include overall number, of Parkinson’s pa-
Cholinesterase inhibitors stop the people likely to develop Alzheimer’s but tients vary widely, so incidence — the
action of acetylcholinesterase, an currently asymptomatic, as well as other occurrence of new cases within a given
enzyme that breaks down the neu- participants at the pre-dementia stage. time period (for example, per year) —
rotransmitter acetylcholine. This Another treatment strategy, based is a better index for this disease. There
increases the available amount of on the amyloid hypothesis, uses the is a higher incidence of Parkinson’s in
acetylcholine (involved in learning and body’s immune response to attack developed countries but the reason is
memory), which counteracts the and clear amyloid plaques. Trials for unknown, although increased risk of
damaging effect of the disease on active immunization (which trains the the disease has also been reported in
production of this neurotransmitter. immune system to build a person’s rural areas with increased pesticide use.
The fourth drug, memantine, is an antibodies) and passive immunization
NMDA receptor antagonist. Normally, (which transfers already active defen- Symptoms
NMDA receptors bind the neurotrans- sive antibodies without bolstering the At first, Parkinson’s is charac-
mitter glutamate, allowing calcium to person’s own immune system) have terized by motor problems: slow
enter the neuron. In Alzheimer’s, the both been explored. So far, however, movement; muscular rigidity; poor
damaged cells become overwhelmed these types of therapies have been coordination and instability; and shak-
with calcium, further damaging the inadequate for people with moderate ing in hands, arms, legs, jaw, and face
neurons — a condition called neuro- to severe symptoms. while at rest. As the disease progresses,
nal excitotoxicity. Memantine blocks the shaking, known as resting tremor,
the flow of calcium through NMDA- PARKINSON’S DISEASE may worsen and interfere with walk-
receptor channels. Parkinson’s disease is the second ing, talking, and other simple tasks.
The fifth approved medication most common neurodegenerative dis- Cognitive decline often occurs at later
combines donepezil and memantine. order in humans. Like Alzheimer’s, its stages. Some people develop depres-
Donepezil can be used in all stages of incidence increases with age, with the sion and other emotional changes,
the disease, galantamine for mild to average onset around age 60. About 5 difficulty swallowing and chewing,
moderate stages, memantine for mod- million people in the world’s 10 most skin problems, constipation or urinary
erate to severe stages, and rivastigmine populous countries have Parkinson’s, problems, and sleeping problems.
in all stages. The donepezil/memantine and its frequency is expected to dou- However, the rate and intensity of Par-
cocktail is used to treat moderate to ble by 2030. With 50,000 to 60,000 kinson’s progression vary. Some people
severe Alzheimer’s. cases diagnosed annually in the U.S., become severely disabled, while others
Several clinical trials are now un- the actual figures may be much higher have only minor motor disruptions.
derway to find new and better treat- — especially since early symptoms
ments for Alzheimer’s. The Alzheimer’s can be mistaken for normal aging and Pathology and Causes
Forum currently lists 14 treatments that thus are not reported. Parkinson’s is a motor system
are in the later stages of clinical trials. From 2000 to 2013, the age- disorder caused by the loss of
Overall, however, there is a high failure adjusted death rates for those with dopamine-producing cells neurons

National Institute on Aging, NIH.

Alzheimer’s disease is associated with high levels of the beta-amyloid protein. This protein clumps together and forms plaques, which are
pictured in brown. These plaques can build up between neurons and interrupt their activities. Tau proteins also accumulate and form tangles
— seen in blue — within neurons, disrupting communications.
in the substantia nigra — a midbrain Parkinson’s and Lewy body dementia symptoms. In the future, mitochon-
structure that is considered part of the are sometimes considered different dis- drial molecules could be a potential
basal ganglia. This brain region affects orders, Lewy bodies, accumulations of source of a Parkinson’s biomarker.
movement, reward, and addiction. At proteins in neuron bodies, have been
the cellular level, the death of neurons implicated in both diseases. Lewy bod- Research
likely arises as a result of damage to ies are mainly composed of the protein Scientists can treat mice with
mitochondrial respiration. alpha-synuclein entangled with other the chemical MPTP (1-methyl-4-
Some early-onset cases are linked proteins, including neurofilament, phenyl-1,2,3,6-tetrahydropyridine) to
to mutations in the PARK2 (or ubiquitin, alpha B crystallin, and create an animal model that can pro-
PRKN) gene, which codes for the probably tau protein in neurofibrillary vide further insight into Parkinson’s. In
protein “parkin.” Most types of Parkin- tangles. The Lewy body protein, al- the body, MPTP metabolizes into the
son’s are caused by a combination of pha-synuclein, is involved in dopamine neurotoxin MPP+ (1-methyl-4-phen-
genetics and environment, but an esti- transport in the nervous system. ylpyridinium), which causes a Parkin-
mated 15 to 25 percent of people with There is no definitive test for son’s-like loss of cells in the substantia
adult-onset Parkinson’s have a known Parkinson’s so, without accepted bio- nigra and cognitive deficits. However,
relative with the disease. Genes like markers, diagnosis is based on medical MPTP does not perfectly mimic the
alpha-synuclein (SNCA), repeat kinase history and neurological tests that can symptoms of human Parkinson’s dis-
2 (LRRK-2), and glucocerebrosidase include brain scans. Accurate diagnosis ease, including the motor deficits.
(GBA) also point to the importance can be difficult, because some non-Par- Research on using stem cells to
of genetics as a causal factor. While kinson’s conditions display similar replace damaged dopamine neurons

in Parkinson’s patients has shown patient’s symptoms are originating, AMYOTROPHIC LATERAL
promise. There are two types of stem using MRI or CT scans. Most often, SCLEROSIS
cells: the more flexible (and con- the problem areas in the brain are the ALS is a group of progressive,
troversial) fetal tissue and induced thalamus, the subthalamic nucleus, ultimately fatal motor neuron diseases.
pluripotent stem (iPS) cells, which and a portion of the globus pallidus ALS is also called Lou Gehrig’s disease
are specialized adult (often blood or (part of the basal ganglia). After the after the renowned New York Yankee
skin) cells that have been repurposed imaging, microelectrode recording first baseman, who was one of the
into a generalized embryonic state. — which involves a small wire that most famous victims of the disease.
There have been successful lab studies monitors the activity of nerve cells in ALS forced Gehrig to retire at age
using iPS cells, and positive to mixed the target area — is sometimes used 36. Gehrig died two years later. ALS
results in clinical studies with the fetal to further localize problem areas in afflicts as many as 15,000 Americans,
stem cells. A Kyoto University study, the brain. This approach has proven most between the ages of 50 and 70.
published in August 2017, transferred to be highly successful with a segment Although men are slightly more likely
human iPS cells into the brains of of patients. than women to develop the disorder,
monkeys treated with MPTP. Two
years after this transplantation, the
treated monkeys were shown to have
healthy DA neuron integration,
ALS is also called Lou Gehrig’s disease

growth, and even functioning in
the striatum.
Treatments
Treatment with levodopa
after the renowned New York Yankee
(L-Dopa) temporarily relieves
Parkinson’s motor symptoms but does
first baseman, a famous patient with
not slow disease progression. Ironically, the disease.
the long-term use of L-Dopa can
induce dyskinesia — abnormal and
uncontrolled involuntary movements.
Strategies for treating Parkinson’s
include gene therapy and targeting One treatment still in the that difference lessens with increasing
specific cellular molecules. research stage is a strategy to break age. For unknown reasons, non-His-
A surgical procedure called deep apart Lewy bodies. The idea is to use panic whites are more likely than other
brain stimulation (DBS) is increas- high hydrostatic pressure to break ethnicities to develop ALS. Military
ingly used to treat Parkinson’s pa- apart aggregated alpha-synuclein veterans’ likelihood of developing the
tients whose symptoms, including fibril plaques, like those found in disease is as much as 1.5 to 2 times
rigidity, tremor, slowed movement, Lewy bodies, and return the protein higher than the rate in the general
and mobility problems, do not to its properly functioning form. An- population — possibly due to expo-
respond adequately to medication. other novel approach to preventing sure to environmental toxins like
The DBS technique implants a small Parkinson’s was suggested by epide- lead and pesticides.
neurostimulator device — like a pace- miological studies that found that
maker — that sends electrical impuls- the disease is less common among Symptoms
es that interfere with and block brain coffee drinkers and cigarette smok- Unlike the previously discussed
signals that cause the motor symp- ers. If caffeine and nicotine offer neurodegenerative disorders, general-
toms of Parkinson’s. Before implant- protection, this could reflect some ly neither cognition nor personality
ing a neurostimulator into the brain, central action that benefits the brain’s is affected in individuals with ALS.
the neurosurgeon locates where the dopaminergic systems. Early ALS symptoms include muscle

weakness, twitching, and eventual Research and Treatments common among Japanese, Chinese, or
paralysis in the hands and feet. These There is no cure for ALS, nor African populations. The HD variant
symptoms gradually spread as patients has any medication been of the HTT gene is dominant; if one
lose strength and the ability to move, found that can stop or reverse its parent has a single copy of the HD
speak, and eat. Most ALS patients progression. But the FDA has ap- gene variant and the other parent has
die within three to five years after proved edaravone and riluzole for normal HTT genes, a child has a 50
symptoms appear due to nerve dam- treating ALS. Edaravone, an antioxi- percent chance of inheriting the HD
age affecting the respiratory muscles. dant that inhibits the production of variant and developing the disease.
However, 10 percent of ALS patients cell-damaging free radicals, can The most common form of HD be-
— like the physicist Stephen Hawking ameliorate disease symptoms. Riluzole gins earlier than most progressive brain
— survive 10 years or more. decreases glutamate levels, and has diseases, becoming active when people
been shown clinically to extend the life are in their 30s and 40s. Death occurs
Pathology and Causes of ALS patients by a few months. 15 to 20 years after a patient becomes
Motor neurons connect the brain A therapy called NurOwn, devel- symptomatic. Juvenile HD begins in
to the spinal cord and to the voluntary oped by BrainStorm Cell Therapeutics, childhood or adolescence, and juvenile
muscles throughout the body. In ALS, is entering a phase 3 clinical trial (to HD patients usually die 10 to 15 years
the motor neurons degenerate and then confirm drug safety and efficacy over after their symptoms appear.
die. Without this neural communica- a longer testing time) after showing
tion, a person’s voluntary muscles weak- promise for halting or reversing ALS Symptoms
en, begin twitching, and finally atrophy. progression. NurOwn uses undifferen- Signs of HD begin with irritabil-
Only 5 to 10 percent of ALS cases tiated stem cells from the patient’s own ity, mood swings, depression, small
are due solely due to genetic factors — bone marrow, which are then modified involuntary movements (called cho-
a condition called “familial ALS”; the to boost the production of neurotroph- rea), poor coordination, and difficulty
non-familial disease is called “sporadic ic factors that support and protect making decisions and learning new
ALS.” While several genes have been neurons destroyed by the disease. information. As the disease progresses,
identified that increase susceptibility For those with the SOD1 mu- the chorea becomes more pronounced
to ALS, there is no clear pattern of in- tation, there is also hope for a gene and patients have increasing trouble
heritance. Among cases with a genetic silencing technique using an artificial with voluntary movements like walk-
component, about 25 to 40 percent RNA snippet. Lab tests in mouse ing, speaking, and even swallowing.
are caused by a harmful mutation in models have preserved muscle strength Their cognitive problems also worsen.
the C9ORF72 gene. Some individuals and motor and respiratory functions, While juvenile HD displays the same
with this mutation show symptoms and delayed disease onset and death. symptoms as the more common form,
of both motor neuron and dementia This treatment has also safely silenced it also includes slow movements,
disorders, a condition known as ALS- SOD1 in the lower motor neurons of clumsiness, frequent falling, rigidity,
FTD (ALS-frontotemporal dementia). nonhuman primate models. slurred speech, and drooling. School
Another 12 to 20 percent of heredi- Participation in a multidisciplinary performance declines as thinking and
tary cases result from mutations that ALS clinic, an ALS Association Certi- reasoning abilities become impaired,
prevent the SOD1 gene from cod- fied Treatment Center of Excellence, or and seizures occur in 30 to 50 percent
ing for superoxide dismutase — an a Recognized Treatment Center can also of children with this condition.
enzyme that catalyzes the breakdown improve ALS patients’ quality of life.
of cell-damaging superoxide radicals Causes and Genetics
into more benign molecular oxygen or HUNTINGTON’S DISEASE In 1993, Huntington’s disease
hydrogen peroxide. These and other Huntington’s disease (HD) is a was found to be caused by mutations
hereditary forms of ALS, such as those heritable disease that impairs voluntary in the HTT gene, which codes for the
involving UBQLN2 and VEGF genes, movement and cognition. The dis- huntingtin protein, located on chro-
provide valuable insights into the me- ease afflicts 3 to 7 people of 100,000 mosome 4. The protein likely inter-
chanics of the disease. people of European descent, but is less acts with other proteins involved in

signaling, transport, binding to (voluntary movement) and the cortex only the second product approved for
proteins and other structures, and pro- (cognition, perception, and memory). treating HD. Furthermore, there is
tecting the cell from self-destruction. now evidence for viable HD biomark-
The disease mutation involves an ab- Detection and Treatments ers. Tau (which turns up regularly
normal number of repeats of a three- In late 2015, Ionis Pharmaceu- in neurodegenerative diseases) and
part (trinucleotide or triplet) snippet ticals began the first human neurofilament light chain, a compo-
of DNA in the HTT gene. This trials of a “gene silencing” or “hunting- nent of the neuronal cytoskeleton, are
sequence of the nucleotides cytosine, tin lowering” drug. IONIS-HTTRx is found at elevated levels in cerebro-
adenine, and guanine (CAG) normal- an antisense oligonucleotide — a spinal fluid of HD patients. A recent
ly repeats 10 to 35 times, but occurs single strand of a chemically modified study points to the neurofilament
from 36 to 120 or more times in the DNA designed to interrupt and light chain, and to a lesser extent tau,
mutation. The greater the number of decrease the mutated form of the as viable HD biomarkers. Interest-
CAG repeats, the earlier symptoms huntingtin protein produced in HD ingly, the neurofilament light chain is
appear and the more severe they are. patients. The drug is now in phase 2 also being investigated as a biomarker
The “expanded” huntingtin protein trials comparing it to a placebo in for ALS and other neurodegenera-
is susceptible to clumping. While early-stage HD patients who are tive diseases. In mouse studies, the
aggregated huntingtin proteins don’t randomly assigned to treatment or amount of neurofilament light chain
cause cell death directly, they disrupt control groups. found in the animals’ cerebral spi-
the mitochondrial electron transport In spring 2017, the FDA ap- nal fluid and blood increased before
chain, initiating a cascade of neuronal proved the drug deutetrabenazine for neurological signs appeared, likely
dysfunction and death. Brain areas treating chorea associated with Hun- coinciding with the development of
most often affected are the basal ganglia tington’s disease. This is reportedly brain lesions.

CHAPTER
16
Kinds of A
s you’ve seen in previous
chapters, neuroscientific
research has made astounding
advances in the past 150 years. The
Research development of new research tools

and technologies has driven these
discoveries, from the first images
of individual neurons to revealing
the genetic causes of neurological
disorders. This chapter introduces
you to some of the most important
research methods used to understand
the brain, including unusual types
of microscopy, animal models, and
cutting-edge molecular techniques.
TOOLS FOR ANATOMY

Anatomy is the study of
structure — most often, the
structure of biological organisms. For
the brain, anatomy starts with the
structure of neurons, which are among
the most complex and diverse cell
types in our bodies. Scientists were
first able to observe neurons in the late
19th century, thanks to histological
techniques that start with a very thin
slice of brain tissue to which scientists
apply stains or other compounds that
add contrast or color to specific
structures. They then view the tissue
with a light microscope, which passes
visible light through the thin slice and
lenses that make the structures look up
to 1,000 times larger than they do
with the naked eye.
Histology is the study of how cells
form tissues. Histological techniques
can reveal changes in the density of
cell types or the presence of molecules
that can suggest a particular disease.
These techniques have helped illu-
minate the brain changes underlying
some neurodegenerative disorders. For
example, histological methods have
shown that an enzyme that breaks
down acetylcholine is associated with
Brain Facts 105

16 Kinds of Research
the brain plaques and tangles of Alz- imaging, or MRI. Developed in the concentrations, etc.) is provided. In an
heimer’s disease. And in the brains of 1980s, MRI is widely used by research- isolated brain slice, researchers can
Parkinson’s disease patients, histology ers and doctors to view a detailed im- better identify the exact cell they are
has revealed the death of neurons that age of brain structure. MRI equipment recording from and can infuse drugs
normally control movements through uses radio waves and strong magnets into the Petri dish to determine their
dopamine signaling. to create images of the brain based on effects on the brain.
Long after light microscopes gave the distribution of water within its Using these methods, scientists
scientists their first glimpses of neu- tissues. MRI is harmless and painless to have made critical discoveries about
rons, a debate bubbled in the scientific the person being scanned, although it synaptic plasticity — the capacity of a
community: Are neurons individual does require sitting or lying in a narrow synapse to become stronger or weak-
cells or a mesh of physically intercon- tube, and the procedure can be quite er in response to sensory inputs or
nected cell bodies? Neurons are so noisy. With an MRI scan, researchers other activity. For example, repeatedly
densely packed that the answer wasn’t can tell the difference between the stimulating a neuron by training an
clear until the 1950s, after the devel- brain’s gray matter and white matter. animal in a particular task, or by direct
opment of a new technology called Gray matter consists of the cell bodies electrical stimulation, increases the
electron microscopy. Electron micro- of neurons, as well as their dendrites synaptic strength and the chance that
scopes can produce useful detailed and synapses. White matter mostly the downstream neuron will react to
images of cellular structures magnified contains axons wrapped in the fatty the incoming signal.
many 100,000s of times by directing myelin coating that gives these regions A disadvantage of electrophysiolo-
a beam of electrons through very thin their white color. Based on the distri- gy, as described above, is that the tech-
slices of tissue, then enlarging and bution of water in the tissues, MRI niques are highly invasive. However,
focusing the image with electromag- images clearly differentiate between another method, called electroenceph-
netic lenses. With this technology, cerebrospinal fluid, the water-rich cells alography or EEG, is able to record
researchers were finally able to see that of gray matter, and fatty white matter. human brain activity without invasive
neurons are not physically continuous or harmful procedures. In EEG, about
but, instead, are individual cells. TOOLS FOR PHYSIOLOGY 20 thin metal discs are placed on the
Although they are individual cells, Information is conveyed along scalp. Each disk is connected by thin
neurons do act in networks, communi- the neuronal pathways that wires to a machine that records the
cating across small gaps called syn- crisscross through our brains as activity of neurons near the brain sur-
apses, where the axon terminal of one electrical activity traveling down axons. face. This approach has been especially
cell meets a dendrite or cell body of To study this activity, researchers useful for understanding epilepsy and
another cell. One method for mapping measure changes in the electrical the stages of sleep. However, it does
the signaling pathways within these charge of individual neurons using not provide information at the level of
networks involves injecting radioactive techniques of electrophysiology. A thin individual neurons.
molecules or “tracers” into the cell glass electrode is placed inside a Researchers who need to look at
body of a neuron. Researchers monitor neuron to measure the voltage across individual neurons in a living brain can
the movement of radioactivity down its cell membrane, which changes use a technique called two-photon mi-
the neuron’s axon, showing where when the neuron is activated. This croscopy. A lab animal such as a fly or
that neuronal path leads. A similar technique can measure neuron activity mouse must be genetically modified so
technique involves tracers that can inside the brains of living lab animals that some of its neurons produce a pro-
actually travel across synapses, from such as rats or mice, enabling scientists tein that glows when a laser beam shines
one neuron to the next. Scientists have to study how neurons transmit on them. Two-photon microscopy has
used such tracers to map the complex electrical information in their normal enabled scientists to understand chang-
pathways by which information travels physical context. Alternatively, a slice es in the brain during normal processes
from the eyes to the visual cortex. of brain can be kept “alive” for a short like learning, as well as changes that
Another technique for examining time in a Petri dish, if the right occur over the course of a disease — for
brain anatomy is magnetic resonance environment (temperature, pH, ion example, watching how the branches on

Kinds of Research 16
neurons near Alzheimer’s-like plaques The normal HTT gene has about a previously possible. This tool, called
break down over time. dozen repeats of a small stretch of CRISPR (which stands for Clustered
DNA within the gene, but Hunting- Regularly Interspaced Short Palin-
TOOLS FOR GENETICS ton’s patients can have more than dromic Repeats), evolved as a bacte-
The human genome is made 100 of these repeats. Researchers now rial immune system that targets viral
up of 3 billion pairs of DNA use DNA chips or microarrays to invaders. Scientists have harnessed
letters or “bases.” This multitude of identify such variations in copy num- CRISPR’s components to home in
adenine (A), cytosine (C), guanine (G), ber. The “array” of a microarray refers on specific DNA sequences in lab
and thymine (T) bases comprises an to the thousands of spots arrayed in animals and human cell cultures. By
estimated 20,000 genes that spell out rows and columns on the surface of tethering DNA-cutting enzymes to
instructions for making proteins, along the chip; each spot contains a known this targeting system, scientists can
with regulatory and other non-coding DNA sequence or gene, which can recreate mutations found in patients
DNA regions whose functions are not grab onto corresponding bits of the with neurological disorders, or even
fully known. Scientists study genetics genome being analyzed. Using this insert new bits of DNA to test their
in many ways, such as following tool, scientists are able to compare effect. With CRISPR, scientists have
diseases or other traits through family DNA samples of two people, perhaps been able to mimick Alzheimer’s in
pedigrees or identifying the exact order one healthy and one with a disorder, rodents, in order to study the disease
of DNA bases (the DNA “sequence”) to see if certain pieces of DNA are and its potential treatments. CRISPR
that code for a given trait. More recent repeated more in one person than in is also used to study mutated human
genetic tools enable scientists to the other. Another type of microar- neurons in Petri dishes. Research-
manipulate genes and other genetic ray helps researchers determine if a ers can observe how mutations that
features to better understand how the patient has a chromosomal translo- cause autism, Parkinson’s disease,
brain works and how to treat it in cases cation — a chunk of a chromosome or other conditions affect neuronal
of dysfunction or disease. that has been misplaced onto growth and function.
Scientists often don’t know which another chromosome. Optogenetics is another fasci-
gene or other DNA feature controls a Recent years have seen great ad- nating intersection of genetic tools
trait. At the outset, a particular trait vances in DNA sequencing methods, with brain science. This ingenious
could be encoded on any of the 23 allowing researchers to more efficiently technique allows researchers to control
pairs of chromosomes in a typical and affordably explore the exact DNA brain activity with flashes of light.
human cell. But with genetic linkage sequence that might underlie brain Scientists genetically modify a lab
studies, researchers have begun to map disorders. In the early 2000s, the Hu- animal like a mouse so that its neurons
gene locations. First, researchers must man Genome Project made public the produce a light-responsive protein.
identify another trait with a known vast majority of the human genome Then, optical fibers are inserted into
chromosomal location that tends to sequence; in the years that followed, the brain to allow light to shine on
be inherited with or “linked” to the the science of genomics has enhanced those neurons — either activating
trait of interest. This technique, which scientists’ understanding of brain func- or silencing them. Optogenetics has
narrows down the likely location of tion at the level of genes, cells, and helped scientists better understand
the gene of interest, was the first step circuits. Genomics can help identify how neurons work together in circuits.
toward identifying the genetic basis of genetic variations that cause conditions This technique has also been used to
many neurological disorders. ranging from depression to schizophre- control animal behaviors ranging from
When you think about muta- nia to movement disorders. sleep to drug addiction.
tions, you probably think of harmful Genetics research now goes far Oddly enough, genetics is not
changes in one or several DNA bases beyond reading the sequence of bases always about genes. As mentioned
within a gene. But some disorders re- in the genome. In the last few years, above, much of the human genome
sult from an overabundance of copies scientists have harnessed a molecular contains DNA sequences that are not
or repeats of a stretch of DNA. This tool that can edit the genome more genes, whose job is to regulate gene
is the case with Huntington’s disease. precisely and efficiently than was activity. These regulatory sequences,

and the enzymes that make changes have mutations in the KMT2D gene that strengthen synapses so the neuro-
to them, help determine under what — and some patients carry the muta- nal response is greater the next time
conditions (in what cells, at what age, tions in only some of their cells. In ad- Aplysia is stimulated. Many of the
etc.) a gene is expressed or repressed. dition, people with Kabuki syndrome molecules and processes identified in
These epigenetic changes occur in may have mutations in other genes that Aplysia’s learning are also involved in
cells when chemical tags are placed on function like KMT2D. human learning.
the regulatory regions of certain genes; It is also possible for a person The fruit fly Drosophila is also
the tags influence whether those genes to carry a mutation but exhibit no commonly used to study behavior,
will be turned on or off. In the past outward signs. Fragile X syndrome, the especially how genes control behavior.
decade, epigenetics research has begun most common form of congenital intel- For example, variations in a gene called
to clarify the role of gene regulation lectual disability in males, is caused by ‘foraging’ determine whether flies
in brain development and learning. an excessive number of DNA sequence tend to roam around as they eat or sit
Epigenetics has also revealed how (CGG) repeats within the FMR1 gene. in one place. Flies with mutations in
mutations in the regulatory regions of The protein product of the FMR1 another gene called ‘timeless’ don’t have
DNA can cause disease, just as muta- gene, which is important for synapse normal circadian rhythms. Mutations
tions can in genes. function, is disrupted by these repeats. have been identified that affect the full
While some people with elevated num- gamut of Drosophila behaviors — from
Genetics in bers of the sequence repeats may not be aggression to courtship, as well as learn-
Neurological Diseases affected, they are carriers with a risk of ing and memory. Many of the affected
The impact of mutations varies passing it on to their children. genes have correlates in humans.
from person to person, and from dis- Addiction presents one of the
ease to disease. A particular mutation TOOLS FOR BEHAVIOR most pressing challenges in studying
might explain some cases of a disorder To understand how brain human behavior — how to better un-
but not others, or it could be only function drives behaviors in derstand it and how to treat it. Some
one of several genetic changes affect- humans, researchers often turn to lab animals like rats will consume
ing a patient. Lissencephaly is a brain animal models. An eight-inch long alcohol and drugs even if accompa-
malformation in which the surface of marine slug may not look like a very nied by a bitter taste or foot shock.
the brain is smooth, unlike normal promising model of brain function but, Scientists have uncovered changes in
brains whose surfaces have ridges and over the years, the animal known as the brains of animals exhibiting such
grooves. It affects development. Babies Aplysia has helped scientists uncover addiction-like behaviors that mirror
with lissencephaly start having spasms many principles of learning and memo- changes seen in the brains of humans
in the first months of life and develop ry. Aplysia has relatively few neurons with addiction disorders. Interestingly,
drug-resistant epilepsy and severe intel- (around 10,000, compared to approxi- some breeds of rats are very likely to
lectual and motor disabilities. Although mately 86 billion in humans), but exhibit addiction and relapse behaviors
about 70 percent of these patients have some of its neurons are large enough to while others are more resistant. By
mutations in the LIS1 gene, at least two be seen with the naked eye. Aplysia also comparing the genetics of two breeds
other mutations have been associated exhibits simple behaviors that can be of rats with different predispositions to
with the condition. Another complex modified with training. For example, cocaine addiction, scientists identified
genetic condition, Kabuki syndrome, Aplysia will reflexively withdraw its gill genes that were differentially turned
is marked by intellectual disabilities, after receiving an electric shock to its on or off in the two breeds; the study
a distinctive facial appearance, slow tail. It can be trained to withdraw its suggests that these genes, and their
growth in infancy, and other physical gill in response to an innocuous touch epigenetic regulation, play a role in
problems. Kabuki syndrome is hard to which, during training, was paired with susceptibility to addiction. This type
diagnose because some symptoms, such an electric shock. Scientists have of research helps scientists understand
as intellectual disability, range from discovered how the timing of training why some people are more prone to
mild to severe. DNA sequencing has sessions affects learning, and have addiction or relapse, and could suggest
found that most patients, but not all, identified proteins and other molecules ways to identify people at risk.

Behavior is also studied directly

in humans. Early mapping of human
behaviors to specific brain regions was
done by observing personality changes
in people who had lost small regions of
their brain due to injuries or surger-
ies. For example, people who have
lost their frontal lobe often become
inconsiderate and impulsive. Modern
imaging techniques, described in great-
er detail below, also help scientists
to pair brain regions with certain be-
haviors. For example, imaging allows
researchers to see certain brain areas
National Human Genome Resource Institute.

“light up” when a person is shown hu-
man faces, but not when they see faces
of other animals. These techniques are
also useful to better understand brain
disorders — such as identifying brain
regions responsible for auditory hallu-
cinations in schizophrenia.
Because its nervous system is much simpler than that of a mammal, the sea slug Aplysia
was an important animal model in early studies on the neurobiology learning and memory.
TOOLS FOR BIOCHEMISTRY
Although we talk a lot about
the electrical signals transmit-
ted along neurons, the brain also
communicates with molecular and
chemical signals. Neurotransmitters are
chemical messengers that travel across a
synapse, carrying signals from one
neuron to the next. Using a method
called microdialysis, researchers can
monitor neurotransmitters in action.
With thin tubes inserted into the brain,
scientists are able to collect tiny
volumes of liquid from just outside
neurons and then analyze the com-
pounds in that liquid. For example, a
researcher could analyze liquid captured
during learning to identify molecules
that are important for that process.
Microdialysis can also be used
to deliver compounds to the brain.
Paulomelo.adv.
Many drugs have powerful effects on

the brain, so scientists can use these
Drosophila melanogaster, pictured here, is widely used for studying many aspects of the substances to tweak brain function
brain and behavior. in order to understand it better.

Pharmacology, the study of the effects

of drugs, is also dedicated to identi-
fying new drugs to treat conditions
like pain or psychiatric illness, as well
as understanding addiction and other
negative consequences of drug use.
Another important method
employed to study the molecules and
chemicals at work in the brain is mass
spectrometry. Once a sample has been
collected — perhaps by using micro-
dialysis — the compounds it contains
are ionized (given an electric charge)
and then sent through an electric or
magnetic field. The behavior of each
molecule in that field indicates its
mass. That information alone pro-
vides valuable clues for identifying a
molecule. Mass spectrometry has also
been very useful in exploring neuro-
degenerative disorders. For example,
Rama.
one treatment for Parkinson’s disease

Mice are one of the most important animal models in neuroscience research.
causes severe side effects, includ-
ing involuntary movements. With
mass spectrometry, researchers have
identified the location within the
brain where this side effect is caused;
that information could point the way
to interventions that can reduce or
prevent those side effects.
TOOLS USED FOR

HUMAN RESEARCH
Many of the methods we have
discussed are too invasive to
use in humans. But several methods for
imaging human brain function do not
require holes in the skull or other lasting
physical changes. Functional MRI
(fMRI) can be used to follow changes in
the brain activity of a person lying
inside an MRI scanner. The machine is
iStock.com/nattrass.
tuned so that it detects blood flow as

well as differences in oxygen-rich and
oxygen-poor blood, based on the idea
that more active regions of the brain Magnetic resonance imaging (MRI) scans are used to create detailed images of organs like
need more oxygen and nutrients, which the brain.

are supplied by fresh oxygenated blood. megawatt of power or less) into the Although neuroscience has
While this is an indirect indication of brain while others detect the light af- progressed by leaps and bounds since
neuron activity, it can pinpoint brain ter it travels through the brain. NIRS neurons were first viewed under a mi-
activity to fairly small regions. can be used to determine the extent of croscope, many phenomena observed
fMRI provides an indirect view of brain injuries and to monitor oxygen with these techniques are not fully
neuron activity, but magnetoencepha- levels in the brains of patients under understood. For example, mysteries
lography (MEG) detects actual electri- anesthesia. Because of its portability, still surround data obtained with EEG.
cal currents coursing through groups NIRS is very useful for studying brain EEG shows that several different brain
of neurons. When neuron activities are activity during tasks — such as driv- regions have characteristic rhythms
synchronized, their combined electri- ing down the highway — that can’t or oscillations — one pattern in the
cal currents produce weak magnetic take place inside an fMRI scanner. visual cortex, another in the sensory
fields that MEG equipment can detect. Positron emission tomography motor cortex, and so on. Even though
A person undergoing the procedure (PET) detects short-lived radioactive this method of examining brain
sits or lies down, with his or her head compounds that have been injected activity has been used since 1929, the
surrounded by a helmet-shaped device into the bloodstream. The radioac- generation of these patterns (some-
that can sense magnetic fields. MEG tive compounds could be oxygen or times called brain waves) at the level of
has been useful in a variety of studies: glucose, or they might be a neurotrans- neural circuits is not well understood.
from how the auditory cortex responds mitter. PET traces where these com- One branch of neuroscience that
to sounds to identifying where epilep- pounds go in the body. The location can help bridge findings from the
tic seizures start in a patient’s brain. of labeled oxygen can indicate blood microscopic to the whole-brain level is
MEG is useful for detecting rapid flow, while a labeled neurotransmitter computational neuroscience. Research-
changes in brain activity (temporal can show which brain regions are using ers in this field develop theories or
resolution) but it does not provide the that signaling molecule. PET can also models about how the brain processes
precise location of that activity (spatial detect the amyloid plaques that are a information, then test these models
resolution). For this reason, researchers hallmark of Alzheimer’s disease; this against real-world data. For example,
can combine MEG data with fMRI technique could one day enable us to they can examine the data and imag-
data to obtain good anatomical detail identify the disease in its early stages. es from EEG or fMRI, then develop
from fMRI and high-speed readings of Although PET has good temporal res- mathematical models to explain the
brain activity from MEG. olution like MEG, it lacks the detailed underlying neuron and circuit activity.
Near-infrared spectroscopy spatial resolution of MRI. Data from the many methods discussed
(NIRS) is similar to fMRI in that Some methods used in human in this chapter — electrophysiology,
it monitors the flow of oxygenated research can change brain activity. molecular studies, anatomy, and func-
blood as a way to estimate neuron In transcranial magnetic stimulation tional brain scans — can all contribute
activity. A major difference is that (TMS), a coil that generates a mag- to these computational models.
NIRS is only useful for measuring netic field is placed near a person’s This chapter provides an intro-
activity near the surface of the brain head. The magnetic field can pene- duction to research methods that have
and does not provide as much detail; trate the skull, temporarily activating driven, and continue to drive, discov-
however, it is far less expensive and or silencing a region of the cortex. ery in neuroscience. As new techniques
cumbersome than fMRI. NIRS is also TMS is used to treat psychiatric and technologies emerge, scientists
more comfortable for the person un- disorders such as anxiety, depression, will add them to their repertoire of
dergoing the procedure, as the setup and post-traumatic stress disorder techniques that can deepen our under-
essentially involves wearing a cap with and could be an effective option for standing of the brain and suggest new
wiring hooked to it. Some of the wires patients with conditions that do not ways to help people whose lives are
transmit harmless laser beams (~1 respond to medications. affected by brain disorders.

CHAPTER
17
Solving
BRAIN-MACHINE INTERFACE
If you know someone
with severe neurological
damage — perhaps cerebral palsy,
Human trauma from a car or motorcycle acci-

dent, a military or sports injury, or a
stroke — you’ve seen, firsthand, how
Problems
communicating with the outside world
and performing daily tasks can be a
challenge. But during the past few
decades, scientists have made impressive
progress in developing technologies that
can bypass such damage. Now brain-ma-
chine interfaces can read the activity of
millions of neurons — through electro-
encephalographic (EEG) activity from
the brain’s surface or from implanted
electrodes — and predict the behavioral
intentions of research participants. These
advances give human and animal
subjects neural control of parts of their
surroundings: from computer cursors to
video games to robotic limbs.
Despite the sci-fi sizzle, most of
the work on electronic brain implants
is derived from basic research on how
animals and people plan and control
various types of movement. Using
hair-thin wires inserted into the brains
of monkeys and rats, scientists first
recorded the firing patterns of cells lo-
cated in the premotor, primary motor,
and posterior parietal cortical areas of
the brain. As the animals performed
repetitive tasks like pressing a lever to
receive a reward, researchers found spe-
cific firing patterns associated with the
motion. Eventually, these patterns were
translated into computer algorithms
that allowed animals to complete a task
via a robotic arm or prosthetic device
simply by thinking about it.
The clinical applications of
brain-machine interfaces quickly became
clear. Neuroscientists and surgeons im-
planted electrode arrays in the brains of
patients with epilepsy, paralysis, stroke,
Solving Human Problems 17
or Lou Gehrig’s disease (ALS), in hopes

of enabling them to communicate and,
someday, move independently. In early
experiments, patients were only able to
gain rudimentary control of a computer
cursor. But a breakthrough occurred in
2011 when, after months of extensive
training, quadriplegic patients learned to
control movements of a third (robotic)
arm — enabling them to grasp a drink
of water or reach out to a loved one.
Honing this technology is allowing
patients to control their own paralyzed
limbs. Electrode chips implanted in
their brains are connected to sleeves
DARPA.
or gloves worn over the injured limbs.

Sending tiny blasts of electricity into the Advances in brain-machine interfaces are leading to incredible treatments, like this
patient’s nerves, located under the sleeve prosthetic arm that is controlled through thought.
or glove, can reanimate paralyzed mus-
cles. But brain-machine interfaces won’t are already thinking of new uses for the thin insulated wire with electrodes at
become part of clinical medicine until technology: restoring memory; enhanc- the tip or along the shaft is inserted
they’re simplified, miniaturized, and ing cognition; and treating diseases such deep into the brain; if both sides of the
made more reliable. Devices that wire- as depression, Alzheimer’s, and epilepsy. brain are to receive implants, a wire is
lessly transmit commands from brain inserted into each side. In a separate
implants are a step in that direction. DEEP BRAIN STIMULATION surgery, a battery-operated pulse gen-
A parallel line of research has Insights into the pathophysiolo- erator is implanted in the upper chest
explored applying this technology in the gy of movement disorders have and connected to the electrodes. When
broader field of neuroprostheses. Neuro- rekindled interest in the use of focused the device is turned on, it starts sending
prosthetic devices not only receive out- electrical stimulation as a form of electrical currents that alter the activity
put commands from a patient’s nervous treatment. The most advanced and of the targeted brain cells.
system, but can also provide input — as precise method — deep brain stimula- The implanted device relies on the
occurs in retinal implants and prosthetic tion (DBS) — was inspired by pacemak- fact that neuronal communication uses
limbs. Prosthetic arms, for example, ers engineered for the heart. Instead of electrical signals. In many movement
have remained frustratingly low-tech, electrodes implanted in the heart, the disorders, an abnormal signal or pulse
but some brain-guided prostheses electrodes of the DBS device are surgical- can gain control of a circuit and can
have integrated nerves and muscles at ly embedded in specific brain regions. easily become magnified. Like someone
several different levels, allowing users to Depending on where the electrodes are shouting in a crowded room, this aber-
perform more precise and natural move- placed, DBS devices can help alleviate rant signal can drown out other activity.
ments, and even enabling some to “feel” the symptoms of some brain disorders. DBS interrupts the shouting, so that
again. Still, even the most sophisticated During most of these implantation normal communication can continue.
neuroprostheses (such as brain implants) surgeries, patients remain awake so that To determine where brain activity
are limited by their number of elec- a neurologist can talk to them and en- needs to be silenced or induced, neu-
trodes and the lifespan of the implanted sure that the electrodes are stimulating rosurgeons must identify the locations
electrodes. Current arrays can only the correct locations. While the patient’s of the problems. The brain areas first
connect to 100 or so neurons, so a more head is held in place with a stereotactic targeted for tremors and Parkinson’s
complex and useful bionic future is still frame, the surgeon drills a dime-sized disease were chosen after years of pains-
far away. Yet scientists and entrepreneurs hole (or smaller) in the skull. Then, a taking neuroimaging, neuroanatomy,

17 Solving Human Problems
Hellerhoff.
Deep brain stimulation uses electrodes implanted deep in the brain, which carry electric impulses to specific brain regions. The power packs
that provide the electricity are implanted in the patient’s back, as seen in this X-ray.
and fundamental research, especially electrical currents to alter neural activ- -tech compared to TMS and DBS.
in nonhuman primate models. Since ity in a specific region of the human A number of studies have sug-
then, deep brain stimulation has been cortex and, indirectly, deeper brain gested that tDCS and tACS might be
used to treat epilepsy, dystonia, To- structures to which it connects. used to improve working memory as
urette’s syndrome and, more recently, During TMS therapy, patients sit well as to relieve chronic pain and the
obsessive-compulsive disorder. Now in a chair while a nurse or technician symptoms of depression, fibromyalgia,
researchers are investigating whether places a magnetic stimulator against their schizophrenia, and other disorders.
the DBS technique can potentially be head. The device painlessly delivers brief However, despite the substantial
extended to mood disorders such as magnetic pulses to the brain, similar in literature, meta-analyses have failed
treatment-resistant depression, as well strength to those generated by magnetic to conclusively prove any effects of
as other complex mental disorders. resonance imaging (MRI) devices, but transcranial electrical stimulation. Cur-
Yet DBS, like any surgical proce- highly targeted. For patients with depres- rently, there is no consensus among
dure, is not without some risks. It is sion, pulses are focused over their left scientists on how these treatments
highly invasive, and potential compli- prefrontal cortex. Here, they generate might work, or even on the best way
cations include infection, stroke, and electrical currents among neurons which, to position the stimulation devices.
bleeding in the brain. It also requires over time, help lift the patient’s mood.
regular neurological follow-up and Similarly, tDCS uses one or two New Types of Drugs
battery changes every 3 to 4 years. milliamperes of direct current to tune Most doctors still recommend
the brain. Although research into medication as the first line of treat-
PSYCHOACTIVE THERAPIES tDCS and its close cousin, tACS, is in ment for neurological and psychiatric
Transcranial Stimulation its early stages, these techniques offer disorders. The antidepressants, antipsy-
A few noninvasive treatments clear advantages over deep brain stim- chotics, and other mind-altering med-
can stimulate cells near the surface ulation and even over TMS. Generally, ications used today have been tested
of the brain: Transcranial magnetic patients report only a slight tingling in extensive clinical trials and remain
stimulation (TMS), transcranial direct or tapping feeling on their head as the largely unchanged from their proto-
current stimulation (tDCS), and tran- therapy is administered. The devices types developed in the 1950s. Each
scranial alternating current stimulation used to administer these therapies are of these classes of drugs is now filled
(tACS) all use magnetic fields or low also cheaper, more portable, and lower with subsequent generations of closely

their brains reacted to the antibodies

against its proteins. Since then, newer
approaches have engineered antibodies
or antibody fragments that bind to
their specific targets without triggering
an autoimmune response. Other re-
Oxford Centre for Functional MRI of the Brain, Oxford University.

searchers have engineered double-duty
antibodies. These use one end to sneak
into the brain by binding to a receptor
on the blood-brain barrier. Once inside,
the antibody’s other end can cut off
production of harmful amyloid-
beta proteins even before plaques form.
By contrast, some therapies aim
to boost helpful peptides and proteins
called trophic factors, which are native
to the brain. Neurotrophic factors
MRI scans can provide detailed images of brain tissue. Here, it displays tissue high in water
and fat content in white. support the growth and survival of
specific groups of neurons. Scientists
related drugs designed to interact more Preliminary trials of drugs that hope to modify these factors to reduce
selectively with their targets, producing use the body’s own immune system to the amount of cell death in various
better therapeutic effects and fewer side confront and clear unwanted proteins neurodegenerative diseases.
effects, in some cases. Nevertheless, from the brain have sparked a great The possible value of at least one
these are just slightly improved copies deal of interest, particularly in the trophic factor — nerve growth factor
of one another. Truly novel drug candi- Alzheimer’s disease community. When (NGF) — has already been demon-
dates are rare, and hard to develop. mice and monkeys receive a vaccine strated in several preclinical and early
One of the biggest challenges in that contains a major component stage clinical trials. NGF slows the
developing new drugs to treat neu- of amyloid plaques, their immune destruction of cholinergic neurons that
rological or psychiatric problems is systems develop antibodies capable of plays a role in the cognitive decline
finding molecules that can cross the traveling to the brain and “tagging” the of Alzheimer’s disease. Injecting NGF
protective blood-brain barrier — tight- amyloid-beta plaques that are the hall- into patients’ brains stimulated the
ly packed endothelial cells lining blood mark of Alzheimer’s disease. This tag- regeneration of these neurons and
vessels restrict the kinds of molecules ging seems to alert microglial cells in induced sprouting of new nerve fibers
that can enter the brain. While this the brain, which head for the plaques around the injection site. In some cas-
barrier’s fortress-like quality is good and try to remove them. In some es, evidence of this sprouting lasted up
for normal function, it prevents most experiments, mice bred to develop an to 10 years after the initial therapy.
drugs delivered by typical means — Alzheimer’s-like disease remembered Brain-derived neurotrophic factor
including pills, patches, injections, how to navigate through a Morris (BDNF) is showing potential for
or enemas — from having any useful water maze, after being vaccinated — treating Alzheimer’s disease, as well
therapeutic effects within the brain. indicating that such vaccines might as Huntington’s, Parkinson’s, ALS,
Scientists have had to design extreme- also relieve symptoms of the disease. and Rett syndrome. Moreover, the
ly tiny molecules or adopt ingenious In the past, however, many Alzhei- effects of boosting BDNF could even
strategies such as nanoparticles that mer’s vaccines have failed in later-stage be stronger than those of NGF. But,
shuttle in drugs, enzymes that activate clinical trials. One reason for these in an interesting twist, the inhibition
molecules after they’ve “snuck through” failures was the development of harmful of some neurotrophic factors such as
the barrier, and antibodies that were side effects. Several human participants the neurite outgrowth inhibitor might
specifically engineered for the brain. experienced severe inflammation when also benefit patients. Studies have

17 Solving Human Problems
found that neurite outgrowth inhibitor show disease-associated changes. investigating associations between genet-
is upregulated in the early stages of Data from predictive neuroimaging ic and cellular mechanisms and various
motor disease, and having too much of can also be useful for guiding person- mental disorders. A single biological
it around could prevent nerve regen- alized treatment options and assessing cause for a mental disorder is hard to pin
eration. Scientists are now conducting a treatment’s clinical effectiveness. down — in fact, many skeptics say it is
clinical trials in which patients with In studies of major depression, for impossible to understand mental illness
ALS and spinal cord injuries receive example, patients whose brain scans solely by understanding the brain. Caus-
custom-made antibodies to disable the showed an overactive amygdala (a brain es of mental disorders are very complex
neurite outgrowth inhibitor protein. region involved in emotional process- and not easy to decipher. And yet, recent
Ultimately, the ever-increasing ing) were more likely to respond to technological advances are enabling
global demand for therapies for neuro- psychotherapy. However, patients who scientists to decipher more of the brain’s
logical and mental diseases is a strong exhibited higher activity in the anterior mysteries. Researchers can look deeper
motivator for scientists and doctors in insula (another brain region involved into the brain with imaging technology,
this field. in emotions) tended to improve with map the circuits underlying specific
medication, but not with psychother- mental states, and study how chemical
PREDICTIVE NEUROIMAGING apy. In the future, psychiatrists could levels change in individual neurons. Bio-
AND PERSONALIZED offer patients the best possible course of markers reflect these physiological con-
MEDICINE treatment based on their own biological ditions, and studying them could lead
As we gain understanding of characteristics, rather than relying only to better targets for treatments. If chosen
the anatomical and functional on symptoms or treatment preferences. carefully, biomarkers might even provide
changes underlying neurological useful ways to compare the effectiveness
illnesses, it becomes increasingly clear CELLULAR MARKERS of treatments between patients, as well
that these changes provide clues for In the past few years, a as in future clinical trials.
earlier detection — even before growing number of clinicians
symptoms appear. Many disorders, and scientists have rejected the bound- CELL TRANSPLANT
such as Alzheimer’s disease, are accom- aries of conventional DSM (Diagnos- To find new treatments for
panied by specific brain activity and tic and Statistical Manual of Mental schizophrenia, stroke, Parkin-
structural changes that can be tracked Disorders)-defined diagnostic proto- son’s disease and other debilitating
over time using MRI. By comparing cols that mental health professionals diseases, researchers around the world
this information with a baseline model usually rely on. Rather than analyzing are turning to stem cells to study the
of a healthy brain, researchers hope to symptoms such as sadness, fatigue, or biology of the diseases and disorders.
predict which patients might one day lack of sleep, the focus has shifted to These undifferentiated cells — from
develop neurological problems. finding biological markers that provide embryos or from certain adult tissues
Although it is still too early for objective indices of those symptoms. — have the remarkable potential to
these “markers” to be used as clinical Much like neuroimaging, cellular develop into any of the three major cell
reference points, they could pave the markers could be used to predict a pa- types of the brain: neurons; astrocytes,
way for objective diagnoses of brain tient’s risk and diagnosis before disease which nourish and protect neurons; and
disorders, much as electrocardiograms symptoms become obvious, as well as oligodendrocytes, which surround axons
and laboratory tests are currently used indicate how a patient may respond to and enable them to conduct signals
to reveal heart problems. The first certain treatments. The markers may efficiently. Scientists hope that stem cells
step in this process is to produce a be proteins, lipids, hormones, nucleic transplanted into the brain might be
generic brain template by averaging acids, or other compounds that can be able to replace and repair neural cells
the images from hundreds of random- detected in samples of blood, urine, that were lost due to disease or injury.
ly selected MRI scans. Scientists can saliva, or cerebrospinal fluid. In mice, stem cell therapy has re-
then use machine-learning software to Although neuropsychiatric research versed the signs of serious spinal cord
characterize the sets of healthy brain on biomarkers still lags behind other injury. Within weeks of treatment,
scans and the sets of scans known to fields such as oncology, researchers are researchers observed that previously

paralyzed mice could walk again. So

far, only a few small trials of fetal and
stem cell grafts have been conducted in
humans. Some of the patients treated
showed meaningful recovery from
otherwise hard-to-treat disorders like
stroke and Parkinson’s. Other trials
were not successful, with replacement
cells starting to produce excessive
amounts of dopamine.
Thus, there are several challenges to
overcome before successful use of neural
stem cell transplant therapy. Embryonic
cells and adult stem cells are difficult to
harness and transplant into the brain.
Controlling where and how stem cells
differentiate into the necessary replace-
ment cells is also tricky. Furthermore,
stem cells carry a risk of being rejected
by the recipient’s immune system.
Scientists have recently discovered how
Stem cell and gene therapies hold huge potential for treating brain diseases. Therapeutic
to convert a patient’s own brain cells genetic material can be introduced in the brain though engineered viruses, while stem cells
directly into dopamine neurons, which can be used to replace damaged or diseased cells in the brain.
eliminates many risks, but the proce-
dures are far from standard. None of adenovirus vectors have also been gene-editing technologies goes far
them has yet been approved by the U.S. evaluated in early-stage human trials beyond direct therapeutic applications.
Food and Drug Administration. for treating brain tumors. With CRISPR, dozens of mouse (and
In recent years, a new gene- other animal) models can be made
GENE REPLACEMENT editing method, CRISPR (Clustered much more efficiently, facilitating stud-
As researchers work to improve Regularly Interspaced Short Palin- ies of the brain and mental illness. But
the safety and efficacy of dromic Repeats), has begun to rewrite the technology is still relatively new, and
genetic and cellular treatments, “conventional” gene therapy. The new it’s not perfect. The CRISPR system
neuroscientists are finding new ways to technique uses RNA-guided enzymes can make unintended cuts in the DNA
deliver therapeutic genes into cells that to snip out or add DNA segments to if sequences are similar enough, so that
need them. Designing therapies able to a cell, allowing researchers to make unintended mutations could arise that
breach the blood-brain barrier is a extremely precise changes in a cell’s affect the health of the animal being
challenge. Recent research has shown genome. Neuroscientists have already studied. In addition, this technology is
that small viruses with healthy genes used CRISPR to repair part of a gene not yet useful for treating complex con-
tucked inside are able to cross the that produces toxic protein aggregates ditions like schizophrenia and autism,
blood-brain barrier and replace faulty in the brains of mouse models of which are thought to involve multiple
genes. Currently, adeno-associated Huntington’s disease. When scientists genes. As with all new technologies,
virus and lentivirus seem to be the looked at the mouse brains a few weeks the ethical issues of using CRISPR as a
safest and most efficient vectors for after the procedure, the aggregated gene therapy in humans are being hotly
gene therapy. These vectors are being proteins typical of Huntington’s were contested. Only time will tell whether
used in clinical trials in patients with almost gone, and the animals’ motor CRISPR can be added to the expanding
Parkinson’s and for some rare genetic abilities had amazingly improved. list of technologies that solve problems
diseases. Herpes simplex virus and Of course, the usefulness of of the human brain.

CHAPTER
18
Neuroscience B
y this time, you’ve learned a
great deal about your brain
and how complicated it is. The
preceding chapters have mostly looked
in Society at the brain as a part of a thinking,

behaving, and feeling individual.
But you rarely live your life as an
isolated individual. In fact, you prob-
ably interact with a wide variety of
people every day, from bus drivers to
store clerks to your best friend. Those
interactions, along with the interac-
tions of people around you, form the
basis of our society. It makes sense that
what you’ve learned about the brains
of individuals can help you understand
groups of individuals — human societ-
ies — and how they function.
Neuroscientists constantly discover
new things about the forces that drive
the brain. If insights into questions like
“How do I make decisions?” or “What
causes addiction?” can change one per-
son’s life, they can have an even greater
influence on groups of people, some-
times even inspiring them to transform
the societies in which they live.
Many questions require critical
thinking about how the human mind
works: “Who decides what the law
should be?” “What makes laws fair?”
“How can we design the economy, and
what groups of people does it leave
behind?” Answering these questions
requires a thoughtful understand-
ing of the workings of the human
mind. Neuroscience can provide
evidence-based arguments for how to
build a society, rooted in a solid under-
standing of brain science.
It might sound like science fiction,
but the more we discover about the
brain, the greater its potential to trans-
form human society. Scientists need to
grapple with the ethical dimensions of
their work, engaging in conversations
with sociologists, lawyers, politicians,
Neuroscience in Society 18
economists, and philosophers to deter- In one famous case, an individual who than many types of forensic evidence.
mine the best ways to build on their had brain surgery to remove a tumor But recent research has shown that
groundbreaking revelations about the suddenly developed a compulsion human memory is far from perfect,
human brain. to view child pornography. During especially as time passes after a crime.
his trial, the man’s doctor provided As witnesses recall their memories,
NEUROLAW evidence that the surgery had dam- they introduce errors, which are then
In earlier chapters, you aged a part of the brain that typically reconsolidated into new memories.
learned all about decision- suppresses such dark urges. Personality This is true of even the most memo-
making, but many decisions have changes after brain surgeries are not rable events. In a study of New York
more drastic consequences than uncommon — was it possible that his City residents one year after the 9/11
whether to buy a taco or stir fry for terrible fixation was a side effect of his terrorist attacks, their memories of
lunch. Behind every crime that makes life-saving surgery? If so, what should the event differed in 40 percent of
the news is a decision — or a series of his punishment be? If the behavior the details. This doesn’t mean that
decisions — that may have individu- wasn’t his “fault,” what does a just eyewitness testimony is useless, but
als facing the legal consequences of society owe his victims? neuroscience has demonstrated that
breaking the law. As with so many
things (including the brain), the more
closely you look at this issue, the
more complicated it gets.
The more neuroscience reveals to us,

Take addiction, for example. In
the last few decades, the American
prison population has grown by
about 500 percent, largely because
of drug-related arrests. In this book,
the more we must accommodate our
you’ve learned how drug use affects the
brain and is associated with signifi-
social structure to the ramifications
cant changes to the prefrontal cortex of these new discoveries.
(PFC), a part of the brain that oversees
impulse control and suppressing crav-
ings. Those changes in the PFC make
resisting drug use much more difficult.
Seen this way, ongoing drug use looks These are not easy questions to it is far from infallible. Judges and
less like a bad decision and more like a answer. They require us to temper our lawyers must now come to terms with
symptom of a disease: addiction. notions of fairness and justice with this change of perspective.
Now lawyers, judges, and scientists new scientific knowledge. The more Nor is this the first time that
have to decide how drug users should neuroscience reveals to us about the neuroscience has helped to change
be treated by the criminal justice sys- mechanisms underlying memory, per- the way the courts work. Polygraph
tem. Should they continue to be jailed, sonal responsibility, and behavior, the tests, once a staple of television crime
as a punishment for their decision to more we must accommodate our social dramas, have been rejected in many
break the law? Or should they receive structure to the ramifications of these courts (including the United States
therapy or rehabilitation to treat, and new discoveries. Supreme Court) as being unreliable.
help them recover from their altered For another example, consider This decision was based on the work
brain states? Or should they receive eyewitness testimony, a common tool of many scientists, who showed that
some combination of both? What is in the courtroom. Studies have found the physiological reactions mea-
the perfect balance? that the testimony of people who sured by polygraph tests (sweating,
Many examples muddy the waters actually witnessed a crime is very con- increased heart rate, etc.) are not
of decision-making and punishment. vincing to juries — more convincing definitively linked to guilt or lying.

18 Neuroscience in Society
After all, dragging an innocent person activity increases in a part of the brain Another study of male stock trad-
to the police station to submit to a lie called the insular cortex. Scientists hy- ers looked at levels of the hormones
detector test might produce the same pothesize that networks of the insular testosterone and cortisol. Researchers
symptoms. Reliable lie detection tech- cortex interact with other brain areas, took saliva samples from a small group
nology might exist one day, but that including parts of the limbic system of traders every day during a work
day is too far in the future to affect that function in learning, memory and week, before and after the bulk of
current court decisions. emotion, to let the player picture the their work was done. On days when
negative consequences of taking such the traders had higher testosterone
NEUROECONOMICS a risk. Suddenly risking a mortgage levels than average, they took larger
You are constantly payment at the blackjack table might risks. However, higher-than-average
making financial not look so appealing. levels of cortisol (a hormone associated
decisions for yourself. Should you Scientists have also discovered that with stress) correlated with risk-averse
stock up on all of your favorite snacks our hormones play a role in economic behavior. With millions of dollars on
now that you are at the grocery store, decisions. In one case, some partic- the line, hormones could be making
or come back later for the items when ipants in an investment game were the difference between a good day at
there is a big sale? Are you saving
enough for college? Do you like that
new sports car enough to put up with
its poor gas mileage? In recent years,
economists and neuroscientists have
begun collaborating to investigate the
brain processes behind these decisions.
Research into reward pathways
This field, called “neuroeconomics,” and the way your brain promotes
has the potential to significantly
alter the way people think about impulsive behavior can help prevent
the economy.
A driving force behind modern making purchases and decisions
capitalism is the belief that individuals
make rational purchasing decisions that you would regret.
— that everyone acting in their own
self-interest creates a system in which
resources will be distributed as fairly given a dose of oxytocin, a hormone the market and a very bad one.
as possible. Yet that theory doesn’t ex- long associated with social bonding. Neuroscience can change our
plain why so many economic decisions Those who received the oxytocin boost current thoughts about the economy
are irrational, or based on gut instinct were more trusting with their money in many other ways. Research on
and rationalized later. Neuroeconomics and invested larger amounts with a autism spectrum disorders is discov-
is especially interested in those situa- broker. However, if they made invest- ering promising treatments, but also
tions where choices are less clear-cut ments through a computer program revealing opportunities for workplaces
or rational and involve unknown (or rather than a person, the oxytocin had to employ the unique abilities of neu-
unacknowledged) factors and risk. no effect on their investment strat- rodiverse people. Research into reward
To learn more about these deci- egy. These results suggest that social pathways and the way your brain
sions, scientists have measured brain and neurobiological factors interact promotes impulsive behavior can help
activity as people complete economic to play a role in such decisions, and prevent making purchases and deci-
tasks — for example, running brain these kinds of effects are at the heart sions that you would regret. Scientists
scans as people play a simple double- of many economic decisions. More are also studying unconscious biases
or-nothing game. When a player de- research in this area could lead to more and discrimination, in an effort to help
cides to risk it all to double winnings, rational investment strategies. eliminate negative prejudices in hiring

Neuroscience in Society 18
and employment. These are only a few about making children smarter or in- might not have had the ability to
of the practical applications of neu- creasing their chance of getting a per- properly consent?
roscience, and more are anticipated. fect math score on their SATs? Some The questions raised in this chap-
Sometime in the near future, neuro- people believe that all children have ter have no easy answers. Your respons-
science could have all the tools needed the right to be genetically enhanced, es could depend on your religion, your
to design a better, and more inclusive, while others insist that they retain the socioeconomic class — and, yes, on
economic system. right not to be enhanced. the activity of your hormones, your
And who would have access to neurotransmitters, and the progressive
ETHICS AND THE FUTURE these enhancements? Will they only maturation and aging of your nervous
OF NEUROSCIENCE be available to children of the rich and system. The brain is the most compli-
Modern science has powerful, leaving most of us behind? cated structure in the known universe,
the potential to change Similar questions can be asked of other and investigating its mysteries seems to
some of the most fundamental beliefs therapies, like drugs or devices like produce as many questions as answers
of our society. Brain science, in particu- transcranial stimulation, which alter — and these questions are scientific,
lar, has raised many ethical issues. the brain in order to treat it. ethical, legal and social. But the prog-
Consider the history of brain research, In the past, these questions were ress of science has always stirred up
where early attempts to understand the often posed by authors of science fic- “inconvenient” questions about ethical
brain started or exacerbated practices tion. But with the startling technolog- behavior, social conventions, and the
such as phrenology, eugenics, forced ical advances of recent decades, these proper use of our institutions. Asking
sterilization, and unnecessary loboto- real-world challenges might be closer those questions early will help re-
mies. When the ethical frameworks of than you think. In fact, many scientists searchers and the public work together
science fail, it can incur consequences and doctors already deal with serious to create strong ethical frameworks for
that affect not only individuals, but ethical quandaries created by neurosci- our evolving society.
society as a whole. ence. For example, scientists can detect Science is an ongoing process.
In the future, new technologies specific biomarkers for disorders such Neuroscience has made many ben-
that are already on the horizon will as depression, psychosis, and certain eficial advances, but facts are also
raise serious ethical questions. Genetics types of chronic pain. Are medical evolving as discoveries emerge. We are
is one area under intense scrutiny. As professionals obligated to take steps to only on the very cusp of understand-
you’ve read in this book, you’ve seen treat a disease or disorder that cur- ing the billions of cells and trillions
that many brain diseases have their rently shows no symptoms and might of connections that form the human
roots in your genetic code, and scien- never actually materialize? When is the brain. Stay curious about the neuro-
tists are now able to screen for some right time to intervene? science you read in the news, keeping
of these diseases while children are There are even thornier questions in mind what you have learned in this
in the womb. Emerging technologies to consider: When getting permission book to give you context behind the
might soon help us identify potential to treat the brain in some way, the headlines. You are part of science, too.
problems and alter a child’s genes to organ that gives consent is the same as Dialogues between scientists are as
prevent it. But is it ethical to alter an the organ being treated. How does that vital as dialogues between neuroscien-
unborn child’s genetics to cure autism? affect the idea of “informed consent” tists and society. Creating a forum for
Other genetic diseases, like Hunting- in cases like Alzheimer’s disease or a debate and discussion holds out the
ton’s, will only manifest much later in debilitating brain tumor? Should a best hope of answering questions in
life. Is it acceptable to “pre-treat” this doctor proceed with treatment when ways that advance our society now
disease with genetic alterations? What the patient (that is, his or her brain) and in the future.

Glossary
Acetylcholine A critical neurotransmitter Amyotrophic Lateral Sclerosis (ALS) Autism Spectrum Disorder (ASD) A set
that controls functions such as memory, atten- Commonly known as Lou Gehrig’s disease, of conditions characterized, in part, by
tion, sleep, heart rate, and muscular activity. ALS causes motor neurons in the brain and impaired social communication and inter-
spinal cord to disintegrate, resulting in loss of action, and narrow, obsessive interests or
Action Potential An electrical charge control of voluntary muscle movements such repetitive behaviors.
that travels along the axon to the neuron’s as walking.
terminal, where it triggers the release of a Autonomic Nervous System A part of the
neurotransmitter. This occurs when a neuron Analgesic A drug that relieves pain without peripheral nervous system responsible for
is activated and temporarily reverses the causing a loss of consciousness. regulating the activity of internal organs.
electrical state of its interior membrane from It includes the sympathetic and parasympa-
negative to positive. Anxiety A state of heightened arousal charac- thetic nervous systems.
terized by intense worry.
Addiction Loss of control over drug intake Axon The fiber-like extension of a neuron by
or compulsive seeking and taking of drugs, Aphasia Disturbance in language compre- which it sends information to target cells.
despite adverse consequences. hension or production, often as a result of
a stroke. Axon Terminal The ends of axons where
Adenosine A neurochemical that inhibits neurotransmitters are released to target cells.
wakefulness, serving the purpose of slowing Apoptosis Programmed cell death induced
down cellular activity and diminishing arous- by specialized biochemical pathways, often Basal Ganglia A group of interconnected
al. Adenosine levels decrease during sleep. serving a specific purpose in the development structures located deep in the brain that play
of an animal. an important role in voluntary movement,
Adrenal Gland An endocrine organ that motor skill learning, and habits. These struc-
secretes hormones. The outer layer (adrenal Arousal A physiological state involving tures include the caudate nucleus, putamen,
cortex) secretes the stress hormone cortisol. changes in the body and brain that motivate nucleus accumbens, globus pallidus, and
The inner portion (adrenal medulla) secretes behavior and enable response to stimuli. substantia nigra.
epinephrine and norepinephrine in concert
with the activation of the sympathetic nervous Astrocyte A star-shaped glial cell in the cen- Benzodiazepines A class of drugs that en-
system in the “fight or flight” response. tral nervous system that nourishes neurons; hance activity of the brain’s primary inhibitory
regulates the formation, maintenance, and neurotransmitter, gamma-aminobutyric acid
Alzheimer’s Disease (AD) A major cause pruning of synapses; and contributes to the (GABA), to produce sedative and anti-anxiety
of dementia in the elderly, this neurodegener- blood-brain barrier. effects. Benzodiazepines are often prescribed
ative disorder is characterized by the death of to treat anxiety disorders and insomnia.
neurons in the hippocampus, cerebral cortex, Attention A state of arousal in which the
and other brain regions. The earliest symp- brain’s sensory processing is directed at a Blood-Brain Barrier A protective membrane
toms of the disease include forgetfulness; dis- limited number of stimuli. Voluntary (en- composed of tightly packed endothelial cells
orientation as to time or place; and difficulty dogenous) attention is a conscious decision lining the brain’s capillaries and highly special-
with concentration, calculation, language, and to focus on a particular stimulus. Involuntary ized astrocytes, which controls the passage of
judgment. In the final stages, individuals are (exogenous) attention is an unplanned focus certain molecules into and out of the brain.
incapable of self-care and may be bedridden. on a change in the environment, such as a
loud noise or sudden movement. Brain Waves Oscillating patterns of brain
Amnesia A memory impairment usually activity that can be detected and recorded
caused by brain damage or disease, or by Attention Deficit Hyperactivity Disorder using electroencephalography (EEG).
drugs such as some anesthetics. People with (ADHD) A condition characterized by
amnesia may be unable to recall events from excessively inattentive, hyperactive, or Brain-Derived Neurotrophic Factor
the past, form new memories, or both. impulsive behaviors. (BDNF) A neurotrophic peptide that supports
the growth and survival of neurons.
Amygdala A structure in the forebrain that Auditory Nerve A branch of the vestib-
is an important component of the limbic ulocochlear nerve that transmits auditory
system and plays a central role in emotional information from the cochlea of the ear to
learning, particularly within the context the brain.
of fear.

Brainstem The major route by which the Computational Neuroscience A field of Depolarization A change in a neuron’s
forebrain sends information to and receives neuroscience research that uses computer pro- membrane potential in which the cytoplasm
information from the spinal cord and pe- grams and algorithms to analyze information becomes more positively charged. Neurons
ripheral nerves. The brainstem includes the about the brain, and develops mathematical must depolarize beyond a certain threshold to
midbrain, pons, and medulla, and it controls, models to explain brain function. generate an action potential.
among other things, respiration and the regu-
lation of heart rhythms. Cones A primary receptor cell for vision lo- Depression A psychiatric disorder character-
cated in the retina. It is sensitive to color and ized by sadness, hopelessness, pessimism, loss
Broca’s Area A region of the frontal lobe — is used primarily for daytime vision. of interest in life, reduced emotional well-
usually the left hemisphere — that governs being, and abnormalities in sleep, appetite,
speech production. Corpus Callosum The large bundle of and energy level.
nerve fibers linking the left and right cerebral
Cell Body Also called the soma, the part of a hemispheres. Dopamine A catecholamine neurotransmit-
neuron that contains the nucleus (with DNA) ter present in three circuits of the brain: one
and the organelles, but not the projections Cortisol A hormone manufactured by the ad- that regulates movement; a second, thought to
such as the axon or dendrites. renal cortex. In humans, cortisol is secreted in be important for cognition and emotion; and
the greatest quantities before dawn, readying a third that regulates the endocrine system.
Central Nervous System The brain and the body for the activities of the coming day. Deficits of dopamine in the motor circuit are
spinal cord. associated with Parkinson’s disease. Abnormal-
Cranial Nerves Twelve pairs of nerves that ities in the second circuit have been implicat-
Cerebellum A large structure located at the can be seen on the bottom surface of the brain. ed in schizophrenia.
roof of the hindbrain that helps to control the Some of these nerves transmit sensory infor-
coordination of movement by making connec- mation; some control the movement of face, Down Syndrome A condition that results
tions to the pons, medulla, spinal cord, and head, and neck muscles; others transmit infor- from the presence of an extra copy of chromo-
thalamus. It also may be involved in aspects of mation to internal organs to regulate functions some 21. This genetic anomaly is associated
motor learning. such as blood pressure and heart rate. with physical and developmental characteris-
tics, including mild to moderate intellectual
Cerebral Cortex The wrinkled, outermost Critical Period A period of heightened disabilities; low muscle tone; and an increased
layer of the cerebrum consisting primarily of plasticity in brain development when certain risk of congenital heart defects, respiratory
neuron cell bodies. experiences and sensory inputs are required problems, and digestive tract obstruction.
for the formation of functional brain circuits.
Cerebrum The largest part of the human Dyslexia A pronounced difficulty with read-
brain associated with higher order function- Declarative Memory Also called explicit ing despite normal intelligence, education,
ing, such as thinking, perceiving, planning, memory, a type of memory that can be con- and motivation.
and understanding language, as well as the sciously retrieved. It includes memory of facts
control of voluntary behavior. (semantic memory) and memory of personal Electroencephalography (EEG) A tech-
experiences (episodic memory). nology used to record electrical activity of
Circadian Rhythms A cycle of behavior or the human brain in response to a variety of
physiological change lasting approximately Default Mode Network A collection of stimuli and activities.
24 hours. brain regions activated during quiet rest.
Endorphins Neurotransmitters produced in
Cochlea A snail-shaped, fluid-filled organ Dementia A decline in cognitive ability that the brain that generate cellular and behavioral
of the inner ear responsible for converting interferes with day-to-day functioning. effects like those of morphine.
sound into electrical potentials to produce an
auditory sensation. Dendrite A treelike extension of the neuron Epilepsy A disorder characterized by repeated
cell body. The dendrite is the primary site for seizures, which are caused by abnormal exci-
Cognitive Behavioral Therapy A form receiving and integrating information from tation of large groups of neurons in various
of counseling used to identify and change other neurons. brain regions. Epilepsy can be treated with
negative thought patterns that can contribute many types of anticonvulsant medications.
to anxiety and mood disorders.

glossary continued
Epinephrine A hormone released by the Gamma-Aminobutyric Acid (GABA) Hippocampus A seahorse-shaped structure
adrenal medulla and specialized sites in the An amino acid neurotransmitter in the brain located within the brain and considered an
brain. During times of stress, epinephrine, whose primary function is to inhibit the firing important part of the limbic system. One
also known as adrenaline, is quickly released of nerve cells. of the most studied areas of the brain, it is
into the bloodstream. It then serves to put involved in learning, memory, and emotion.
the body into a general state of arousal, which Glia Specialized cells that nourish and
enables it to cope with the challenge. support neurons. Histamine A compound with multiple func-
tions in the body. In the brain, histamine acts
Episodic Memory A type of declarative Glucocorticoid Hormones Hormones that as a neurotransmitter to stimulate arousal. Lo-
memory consisting primarily of memory of produce an array of effects in response to cal inflammatory responses in the body trigger
personal experiences. stress. Some of the actions of glucocorti- the release of histamines from immune cells.
coids help to mediate the stress response,
Estrogen A female sex hormone produced while other, slower actions counteract the Homeostasis The normal equilibrium of
primarily in the ovaries. primary response to stress and help to re- body function.
establish homeostasis.
Excitation A change in the electrical state of Hormones Chemical messengers secreted by
a neuron that is associated with an enhanced Glutamate An amino acid neurotransmit- endocrine glands to regulate the activity of
probability of action potentials. ter that acts to excite neurons. Glutamate target cells. They play a role in sexual develop-
stimulates N-methyl-d-aspartate (NMDA) ment, calcium and bone metabolism, growth,
Excitatory A type of neuron (or neurotrans- and alpha-amino-3-hydroxy-5-methylisox- and many other activities.
mitter) that excites target neurons and azole-4-propionic acid (AMPA). AMPA
increases the likelihood of their firing an receptors have been implicated in activities Huntington’s Disease A genetic disorder
action potential. ranging from learning and memory to devel- characterized by involuntary jerking move-
opment and specification of nerve contacts in ments of the limbs, torso, and facial mus-
Executive Function Higher-level processing developing animals. Stimulation of NMDA cles, often accompanied by mood swings,
that takes place in the brain’s prefrontal cortex. receptors may promote beneficial changes, depression, irritability, slurred speech,
Executive function comprises impulse control, whereas overstimulation may be a cause of and clumsiness.
working memory, and mental flexibility. nerve cell damage or death in neurological
trauma and stroke. Hyperpolarization A change in a neuron’s
Forebrain A region of the developing brain membrane potential in which the cytoplasm
that goes on to become the cerebral hemi- Gray Matter Portions of the brain that becomes more negatively charged and there-
spheres and major parts of the limbic system. are gray in color because they are composed fore less likely to fire an action potential.
mainly of neural cell bodies, rather than
Fovea A small, pitted area in the center of the myelinated nerve fibers, which are white. Hypothalamus A complex brain structure
retina where visual acuity is highest, due to a It includes the cerebral cortex as well as s composed of many nuclei with various func-
high density of cones. ubcortical structures. tions, including regulating the activities of
internal organs, monitoring information from
Fragile X Syndrome A genetic condition Growth Cone A distinctive structure at the the autonomic nervous system, controlling
resulting from a mutation in the FMR1 gene growing end of most axons. It is the site where the pituitary gland, and regulating sleep
that causes intellectual disability. new material is added to the axon. and appetite.
Frontal Lobe One of the four subdivisions of Hair Cells Sensory receptors in the cochlea Inhibition A change in the electrical state of
the cerebral cortex. The frontal lobe has a role that convert mechanical vibrations to elec- a neuron that is associated with a decreased
in controlling movement and in the planning trical signals; they in turn excite the 30,000 probability of firing an action potential.
and coordinating of behavior. fibers of the auditory nerve that carry the
signals to the brainstem. Inhibitory A type of neuron (or neurotrans-
Functional Magnetic Resonance Imaging mitter) that prevents a target neuron
(fMRI) A technology that uses magnetic fields Hindbrain The most posterior part of from firing.
to detect activity in the brain by monitoring the brain, comprising the pons, medulla,
blood flow. and cerebellum. Insomnia A sleep disorder in which people
have trouble falling and/or staying asleep.

Interneuron A neuron that exclusively signals Mentalization The ability to understand the Neurodegeneration The progressive
another neuron. mental states and thoughts of others and oneself. destruction and loss of neurons. Alzhei-
mer’s, Parkinson’s, and amyotrophic lateral
Involuntary Movement A movement that Microglia Glial cells in the central nervous sclerosis (ALS) are examples of neuro-
occurs without conscious control, such as system that function as resident immune cells. degenerative diseases.
a reflex.
Midbrain The most anterior segment of Neurogenesis The production and growth
Ion Channel Proteins embedded in the cell the brainstem. With the pons and medulla, of new nerve cells during development and, in
membrane that allow ions or other small the midbrain is involved in many functions, select brain regions, throughout life.
molecules to enter or leave the cell. including regulation of heart rate, respiration,
pain perception, and movement. Neuromodulator A chemical messenger
Limbic System A group of structures deep that alters the strength of a synapse by
within the brain involved in motivation and Migration The process whereby new neurons modifying the production and/or response
emotion. The hippocampus, amygdala, thal- find their proper position in the brain. to neurotransmitters. Neurotransmitters,
amus, and hypothalamus are all a part of the hormones, and immune molecules can all
limbic system. Mitochondria Small cylindrical organelles function as neuromodulators.
inside cells that provide energy for the
Long-Term Memory The final phase of cell by converting sugar and oxygen into Neuron A nerve cell specialized for the
memory, in which information storage may special energy molecules, called adenosine transmission of information and character-
last from hours to a lifetime. triphosphate (ATP). ized by long, fibrous projections called
axons and shorter, branchlike projections
Long-Term Potentiation (LTP) A long-lasting Mood A general state of mind and called dendrites.
increase in synaptic strength resulting from an emotional disposition.
increased number of neurotransmitter recep- Neurotransmitters Chemical messengers
tors on the post-synaptic neuron. Motor Cortex A specialized region in the released by neurons at a synapse for the pur-
cortex involved in the planning and execution pose of relaying information to other cells.
Magnetic Resonance Imaging (MRI) A of movement.
technique that uses magnetic fields to create Neurotransmitter Receptors Proteins
a high-quality, three-dimensional image of Motor Neuron A neuron that carries embedded in the postsynaptic cell membrane
organs and structures inside the body. This information from the central nervous system that bind neurotransmitters to alter the
technology is noninvasive and does not expose to muscles. cell’s excitability.
the body to X-rays or other radiation.
Motor Unit A functional unit made up of Nociceptors Nerve endings that signal the
Magnetoencephalography (MEG) A an alpha motor neuron and all of the muscle sensation of pain.
technique that can quantitatively measure the fibers it contains and controls, ranging from
strength of activity in various regions of the a few to a hundred or more. Nodes of Ranvier Unmyelinated gaps in an
brain at millisecond resolution. axon’s myelin sheath along which electrical
Myelin Compact fatty material that sur- impulses travel.
Medulla Also called the medulla oblongata, a rounds and insulates the axons of some
structure of the brainstem that controls basic neurons and accelerates the transmission Nondeclarative Memory Also called
functions like swallowing, breathing, and of electrical signals. implicit or procedural memory, a type of
heart rate. long-term memory that is stored and retrieved
Narcolepsy A sleep disorder resulting from without conscious effort.
Melatonin A hormone produced in the pine- the loss of orexin neurons in the hypothala-
al gland that regulates responses to light-dark mus that causes pronounced sleepiness during Norepinephrine A catecholamine neu-
cycles and induces sleep at night. the day. rotransmitter produced both in the brain and
in the peripheral nervous system. Norepi-
Membrane Potential The voltage difference Nerve Growth Factor (NGF) A substance nephrine is involved in arousal and sleep
between the inside and outside of a neuron. whose role is to guide neuronal growth during regulation, mood, and blood pressure.
The typical membrane potential of a neuron embryonic development, especially in the
at rest is -70mV. peripheral nervous system. Nerve growth Nucleus Accumbens A region at the base of
factor also probably helps to sustain neurons the forebrain that is a part of the basal ganglia
in adults. and is important in motivation and reward.

glossary continued
Obsessive-compulsive Disorder An anx- Paralysis The loss of muscle function Positron Emission Tomography (PET) A
iety disorder characterized by uncontrollable, in all or part of the body, usually due to method of measuring brain function based
recurring thoughts (obsessions) and repetitive nerve damage. on the detection of radioactivity emitted
behaviors (compulsions) that attempt to when positrons, positively charged particles,
mitigate the obsessions. Parasympathetic Branch A branch of the undergo radioactive decay in the brain. Com-
autonomic nervous system concerned with the puters then build three-dimensional images of
Occipital Lobes One of the four subdivi- conservation of the body’s energy and resourc- changes in blood flow based on the amount
sions of the cerebral cortex. The occipital lobe es during relaxed states. of radiation emitted in different brain regions.
plays a role in processing visual information. The more brain activity, the more vivid the
Parietal Lobes One of the four subdivisions picture that is created.
Olfactory Bulbs Round, knoblike structures of the cerebral cortex. The parietal lobe plays
of the brain responsible for processing the a role in sensory processes, attention, Postsynaptic Neuron In a synapse, the
sense of smell. Specialized olfactory receptor and language. neuron receiving chemical messages.
cells are located in a small patch of mucous
membrane lining the roof of the nose. Axons Parkinson’s Disease (PD) A movement Prefrontal Cortex (PFC) A region at the
of these sensory cells pass through perforations disorder caused by the death of dopamine front of the frontal lobe involved in the
in the overlying bone and enter two elongated neurons in the substantia nigra, located in brain’s higher-level functions such as plan-
olfactory bulbs lying on top of the bone. the midbrain. Symptoms include slowness of ning, decision-making, working memory,
movement, muscular rigidity, and walking and inhibitory control.
Oligodendrocyte A type of glial cell in the and balance impairment.
central nervous system that forms myelin. Presynaptic Neuron In a synapse, the
Peripheral Nervous System The nerves neuron transmitting chemical messages to
Opioids Substances that bind to opioid outside of the brain and spinal cord. a target neuron.
receptors in the brain to relieve pain. En-
dorphins are a type of endogenous opioid Photoreceptors A nerve ending, cell, Prostaglandins Small lipid molecules that
produced in the brain. Natural and synthetic or group of cells specialized to sense or enhance nociceptor sensitivity to increase pain
opioids, such as morphine and codeine, can receive light. and prevent further tissue damage.
be prescribed to treat pain.
Pineal Gland A small endocrine gland in the Rapid Eye Movement (REM) Sleep The
Optic Chiasm The place in the brain where brain that produces melatonin. part of the sleep cycle when active dreaming
the optic nerves meet and some axons cross takes place. It is characterized by neocortical
over to the opposite (contralateral) hemi- Pituitary Gland An endocrine organ closely EEG waves similar to those observed during
sphere in animals with binocular vision. linked with the hypothalamus. In humans, waking. This state is accompanied by paralysis
the pituitary gland is composed of two lobes of the body’s muscles; only the muscles that
Optic Nerve The bundle of neurons that and secretes several different hormones that allow breathing and control eye movements
transmit information from the retina to regulate the activity of other endocrine organs remain active.
the brain. throughout the body.
Reflexes Considered the simplest and most
Orexin A hormone produced in the hypo- Plasticity The ability of the brain to modify fundamental movements, they are relatively
thalamus that stimulates arousal. its neural connections to adapt to challenges fixed, automatic muscle responses to particu-
in the environment. lar stimuli, such as the slight extension of the
Oxytocin A hormone produced in the hypo- leg when a physician taps the knee with
thalamus and released by the pituitary gland Pons A part of the hindbrain that, with other a small rubber hammer.
that initiates the release of milk from mamma- brain structures, controls respiration and regu-
ry glands and stimulates uterine contractions. lates heart rhythms. The pons is a major route Retina A multilayered sensory tissue that lines
It is also involved in love and social bonding. by which the forebrain sends information to the back of the eye and contains the receptor
and receives information from the spinal cord cells to detect light.
Pain An unpleasant sensory and emotional and peripheral nervous system.
experience often signaling tissue damage, or Reuptake A process by which released
the potential for damage. neurotransmitters are absorbed for later reuse.

Rods A sensory neuron located in the Stress Any external stimulus that threatens Taste Buds A sensory organ found on
periphery of the retina. The rod is sensitive homeostasis. Many kinds of stress have a the tongue.
to light of low intensity and is specialized for negative effect on the body, but some kinds
nighttime vision. can be helpful. Temporal Lobes One of the four major
subdivisions of each hemisphere of the
Saltatory Conduction The process by Striatum A cluster of neurons deep within the cerebral cortex. The temporal lobe functions
which action potentials “jump” along the brain divided into ventral and dorsal regions. in auditory perception, speech, and complex
unmyelinated nodes of Ranvier, speeding The ventral striatum consists of the nucleus visual perceptions.
electrical transmission. accumbens and the olfactory tubercle, while
the dorsal striatum consists of the caudate and Testosterone A sex hormone produced pri-
Schizophrenia A chronic disorder charac- putamen. The striatum is a part of the basal marily in the testes but also in lower amounts
terized by psychosis (e.g., hallucinations and ganglia and is involved in reward processing. in the adrenal cortex and ovaries.
delusions), flattened emotions, and impaired
cognitive function. Stroke A block in the brain’s blood supply. Thalamus A structure consisting of two
A stroke can be caused by the rupture of a egg-shaped masses of nerve tissue, each about
Schwann Cell A type of glial cell in the blood vessel, a clot, or pressure on a blood the size of a walnut, deep within the brain.
peripheral nervous system that forms myelin. vessel (as may be caused by a tumor). Without The key relay station for sensory information
oxygen, neurons in the affected area die, and flowing into the brain, the thalamus filters out
Selective Serotonin Reuptake Inhibitors the part of the body controlled by those cells information of particular importance from the
(SSRIs) Drugs that block the reuptake of cannot function. A stroke can result in loss of mass of signals entering the brain.
serotonin, increasing its availability in the consciousness and death.
synapse. SSRIs are used to treat depression Trophic Factors Small proteins in the
and other disorders. Substantia Nigra A region of the midbrain nervous system that are necessary for the de-
involved in movement and reward. Parkinson’s velopment, function, and survival of specific
Semantic Memory A type of declarative disease destroys the dopamine-producing groups of neurons.
memory that involves memory of facts. neurons in this region.
Vagus Nerve The tenth cranial nerve, it
Serotonin A monoamine neurotransmitter Suprachiasmatic Nucleus (SCN) A small transmits signals from the brain to the heart,
believed to play many roles, including but not group of nerve cells in the hypothalamus that lungs, and digestive tract.
limited to temperature regulation, sensory express clock proteins, which go through a
perception, and the onset of sleep. Neurons biochemical cycle of about 24 hours. This Voluntary Movement A motor action that is
using serotonin as a transmitter are found sets the pace for daily cycles of activity, sleep, consciously planned and executed.
in the brain and gut. Several antidepressant hormone release, and other bodily functions.
drugs are targeted to brain serotonin systems. Wernicke’s Area A region in the temporal
Sympathetic Branch A branch of the lobe responsible for comprehension
Short-Term Memory A phase of memory in autonomic nervous system responsible for of language.
which a limited amount of information may mobilizing the body’s energy and resources
be held for several seconds or minutes. during times of stress and arousal. White Matter The part of the brain that
contains myelinated nerve fibers. The white
Somatosensory Cortex A region of the Synapse A physical gap between two neu- matter gets its color from myelin, the insula-
parietal lobe responsible for processing touch rons that functions as the site of information tion covering nerve fibers.
and pain signals from the body. transfer from one neuron to another.
Working Memory A temporary type of
Spinal Cord A bundle of nerve fibers run- Synaptic Plasticity The ability of synapses declarative memory, the ability to keep a
ning through the vertebral column that pri- to alter their strength by changing their size, piece of information “in mind.” It is limited
marily functions to facilitate communication shape, number of receptors, and amount of to a small amount of data and, unless trans-
between the brain and the rest of the body. neurotransmitter released. ferred to long-term memory, decays within a
few seconds.
Stem Cells Unspecialized cells that renew Synaptic Pruning The elimination of weak
themselves for long periods through or non-functioning synapses to fine-tune
cell division. neural circuitry.

Neuroscience Resources
The Society for Neuroscience Lundbeck Foundation National Institute of Dental and
1121 14th Street NW, Suite 1010 lundbeckfonden.com Craniofacial Research
Washington, DC 20005 nidcr.nih.gov
(202) 962-4000 The Kavli Foundation
sfn.org kavlifoundation.org National Institute on Drug Abuse
nida.nih.gov
Neuroscience Partner
Stanley Center at Broad Institute
Organizations National Institute of Environmental
broadinstitute.org/stanley
Canadian Association for Health Sciences
Neuroscience Wellcome Trust niehs.nih.gov
can-acn.org wellcome.ac.uk
National Institute of General
Canadian Institutes of Medical Sciences
U.S. National Institutes
Health Research of Health (NIH) nigms.nih.gov
cihr-irsc.gc.ca nih.gov
National Institute of Mental Health
Dana Alliance for Brain Initiatives NIH Institutes and Centers nimh.nih.gov
dana.org National Eye Institute
National Institute of Neurological
nei.nih.gov Disorders and Stroke
Faculty for Undergraduate
Neuroscience ninds.nih.gov
National Heart, Lung and
funfaculty.org Blood Institute
National Institute of Nursing
nhlbi.nih.gov Research
Federation of European
Neuroscience Societies ninr.nih.gov
National Institute on Aging
fens.org nia.nih.gov National Library of Medicine
Foundation for Biomedical nlm.nih.gov
National Institute on Alcohol
Research Abuse and Alcoholism
fbresearch.org National Center for Advancing
niaaa.nih.gov Translational Sciences
Gatsby Charitable Foundation ncats.nih.gov
National Institute of Biomedical
gatsby.org.uk Imaging and Bioengineering
National Center for Complementary
nibib.nih.gov and Integrative Health
International Brain Research
Organization nccih.nih.gov
National Institute of Child Health
ibro.info and Human Development
U.S. National Science
nichd.nih.gov Foundation
La Sociedad Mexicana
de Ciencias Fisiológicas nsf.gov
National Institute on Deafness and
(Mexican Society of Other Communication Disorders
Physiological Sciences) World Health Organization
nidcd.nih.gov
smcf.org.mx who.int

Index
A Anandamide 85 Binge drinking 52, 84
A-beta fibers 24 Antagonists 27 Binocular vision 21
Absence seizures 75 Anterior cingulate cortex 65 Biomarkers 72, 98, 101, 104, 116
Acetylcholine 16, 48, 61, 63, 83–84, 100, Anterior insula 116 Bipolar disorder 77–80
105 Antibodies 90, 100, 115, 116 Blindness 19, 21, 39, 65, 67
Acetylcholinesterase 100 Anticoagulant drugs 95 Blind spot 20
Acquired immune deficiency syndrome Antidepressants 77, 79, 80, 87, 94, 114 Blood-brain barrier 115, 117
(AIDS) 91–92 Antiepileptic agents 94 Brain-derived neurotrophic factor (BDNF)
Action potential 5, 15–16, 67 Anti-inflammatory 57, 94 115
Active immunization 100 Antioxidants 57, 103 Brain imaging 34, 74
Addiction 4, 37, 43, 51, 76–77, 79, Antipsychotic drugs 80, 114 Brain-machine interfaces 112–113
81–86, 101, 107–108, 110, 118–119 Antiretroviral treatment 92 Brain states 59, 61, 119
A-delta fibers 25 Anxiety 37, 59, 63, 72–73, 76–77, 79, Brainstem 11, 13, 22–23, 25, 30, 36, 61,
Adenosine 62 84–85, 91, 111 63
Adenovirus 117 Anxiety disorders 71, 76–78 Brain waves 12, 60, 111
Adrenal cortex 68–69, 79 Aphasia 40 Broca’s area 40
Adrenal glands 69–70 Aplysia californica (sea slug) 35
Adrenaline (epinephrine) 25, 69, 83 APOE 99
Adrenal medulla 69 Apoptosis 48 C
Aerobic exercise 58 Arousal 59, 61–64 C9ORF72 99, 103
Aging 54–58, 100, 121 Ascending pathway 25 Caffeine 62, 82, 86, 102
Agnosia 39 Association fibers 55 Calcium 15, 35, 100
Agonists 27 Astrocytes 15–16, 47–48, 116 Cannabidiol 85
Akinesia 31 Atherosclerosis 70 Cannabinoid receptors 85
Alcohol 46, 52, 59, 62, 81–84 Atonia 60 Cannabinoids 78
Alcohol abuse 31, 84 Attention 51–52, 55, 59, 63–65 Cataplexy 63
Alertness 59, 63, 67 Attention deficit hyperactivity disorder Cell body 14, 16, 46, 106
Allodynia 25 (ADHD) 65, 71, 73 Central nervous system 15, 26–28, 37,
Alpha motor neuron 27–30 Auditory nerve 22 92, 94, 99
Alpha-synuclein (SNCA) 101–102 Autism spectrum disorders 49, 71, 120 Central pattern generators 30
ALS-FTD (ALS-frontotemporal dementia) Autobiographical self 65 Cerebellum 11–13, 30–31, 34, 50, 55,
103 Autoimmune response 115 84, 93
Alzheimer’s disease 5, 8, 56–58, 74, Autonomic (involuntary) nervous system Cerebral cortex 7, 10–11, 13–14, 18, 22,
96–101, 106, 111, 115–116, 121 63, 67, 69 23, 25, 30–31, 33, 48, 55, 72, 73
Amnesia 32, 34, 39 Axon 14–16, 19–20, 23–24, 46–48, Cerebrospinal fluid (CSF) 15, 95, 98,
AMPA receptors 16, 35 50–52, 68, 91, 99, 106, 116 104, 106, 116
Amphetamine 86–87 Axon terminals 14 Cerebrum 10–12, 21
Amygdala 11, 34, 36–37, 43, 61, 64, 78, C fibers 24–25
116 Checkpoint inhibitors 90
Amyloid-beta 98–100, 115 B Chemotherapy 85, 89–90
Amyloid hypothesis 99–100 Basal ganglia 11, 13, 30–31, 34, 41, 61, Cholinergic neurons 115
Amyloid precursor protein (APP) 74, 99 77, 101, 102, 104 Cholinesterase inhibitors 100
Amyotrophic lateral sclerosis (ALS) 27, Basilar membrane 21–22 Chorea 103–104
96, 99, 102–105, 113, 115–116 Benzodiazepines 62, 77, 87 Chromatin 17
Analgesic 25 Beta-blocker drugs 78 Chromosomes 107

index continued
Chronic pain 25, 79, 83, 93–95, 114, Default mode network 65 Endocrine system 66
121 Degeneration 19, 30–31, 57, 84, 91, 97 Endoderm 44
Chronic traumatic encephalopathy (CTE) Delusions 80, 97 Endorphins 25, 83, 94
91, 98 Dementia 54, 57–58, 62, 91–92, 96–101, Entorhinal cortex 34, 99
Circadian rhythms 4, 61–62, 66–67, 108 103 Ephrin 47
Classical conditioning 36 Dendrites 14–15, 46–47, 50, 55, 75, 106 Epidemiological studies 102
Clonazepam 62 Dendritic spines 55–56 Epigenetics 70, 108
Club drugs 87 Dentate gyrus 56 Epilepsy 8, 14, 46, 75, 80, 88, 91, 106,
Cocaine 46, 86, 108 Dependence 77, 81 108, 112–114
Cochlea 21–22 Depolarization 15–16, 60 Epinephrine (adrenaline) 69–70
Cognitive ability 54–55 Depression 5, 8, 59, 67, 73, 76–79, 87, Episodic memory 33–34, 55
Cognitive behavioral therapy 25, 77–80, 91, 93, 100, 103, 107, 111, 113–114, Estrogen 64, 69
83, 94 116, 121 Ethanol 84
Cognitive control 54 Descending pathways 25 Excitatory 14, 16–17, 61
Competitive elimination 51 Designer drugs 87 Excitotoxicity 100
Complex focal seizures 75 Deutetrabenazine 104 Executive function 41–43, 51–52, 73, 86
Computational neuroscience 111 Developmental neurobiology 49 Explicit memory 33
Computerized tomography (CT) 90, 92, Diabetic neuropathy 25 Extensors 27, 29
102 Diffusion tensor imaging (DTI) 52
Concept cells 39 Divided attention 55
Cones 19, 47 DNA sequencing 107–108 F
Continuous positive airway pressure or Dominant mutations 99 Familial ALS 103
“CPAP” machine 62 Donepezil 100 Fight-or-flight response 69, 78
Coordination 30–31, 34, 92–93, 100, Dopamine 16, 30, 37, 56, 61, 63–64, 73, Finches 52
103 77, 79–80, 82–84, 86, 100–102, 106, Flavonoids 57
Cornea 18–19 117 Flexion 27–29
Corpus callosum 10, 12, 51, 75 Dorsal stream 20 Flexion crossed extension reflex 29
Cortical thinning 55–56, 58 Dorsomedial prefrontal cortex 65 Flexion withdrawal 29
Cortisol 17, 67, 69–70, 78–79, 120 Down syndrome 73–74 Flexors 26–27
Cranial nerves 23 Drosophila melanogaster (fruit fly) 67 Fluid intelligence 54–55
Craniotomy 89 Dyskinesia 102 FMR1 72, 108
CREB (cAMP-response element binding Dyslexia 74 Focal seizures 75
protein) 35 Dystonia 114 Follicle stimulating hormone (FSH)
CRISPR 107, 117 68–69
Critical periods 51–52 Forebrain 11–12, 46, 61, 66
Crystallized intelligence 54 E Fovea 19
Cyclic adenosine monophosphate (cAMP) Eardrum (tympanic membrane) 21 Fragile X syndrome 72, 108
35 Ectoderm 44, 46 Free radicals 56, 86, 103
Edaravone 103 Frequencies (pitches) 12–13, 22
Electroencephalography (EEG) 12, 60, Frontal lobe 7, 11, 23, 35, 40–41, 51–53,
D 106, 112 55, 109
Daytime sleepiness 62 Electron microscopy 15, 106 Frontotemporal dementia 98–99, 103
Declarative memory 33–36, 55 Electrophysiology 106, 111 Functional magnetic resonance imaging
Deep brain stimulation (DBS) 77, 79, Emotion 36–37, 52, 65 (fMRI) 39, 43, 52, 65, 110–111
102, 113, 114 Emotional memory 36

G Herpes simplex virus 117 Involuntary (exogenous) attention 64–65
Galanin 61 High blood pressure 57, 59, 62, 70, 95 Involuntary movements 28, 31, 102–103,
Galantamine 100 Hindbrain 11–12, 46 110
Gamma-aminobutyric acid (GABA) 16, Hippocampus 11, 13, 32–36, 37, 55–56, Ion channels 15–16, 35
61, 77 58, 64–65, 70, 74, 78–79, 85, 99 Itch 8, 24–25
Gamma-aminobutyric acid (GABA) Histamine 24, 61, 63
receptors 84 Histology 105–106
Gamma motor neurons 29 HIV-associated neurocognitive disorders J
Ganglion cells 19–21 (HAND) 92 Joints 26–28
Generalized seizures 75 H.M. 32–34, 39
Genes 6, 17, 35, 41, 44, 46, 49, 51, 56, Homeostasis 61–62, 66
67, 70, 72–76, 78–80, 82, 90, 95, 99, Hormones 17, 64, 67–70, 78, 116, K
101, 103, 107–108, 117, 121 120–121 Ketamine 87
Gene silencing 103–104 HTT gene 103–104, 107 Ketogenic diet 75
Gene therapy 90, 102, 117 Human immunodeficiency virus (HIV) Knee jerk 28–29
Genetic linkage studies 107 91
GHB (gamma hydroxy-butyrate) 87 Huntingtin protein 103–104
Ghrelin 69 Huntington’s disease (HD) 31, 103–104, L
Glia 14–16, 44–48, 50, 89, 92 107, 117 Lateral geniculate nucleus 20
Glioblastoma 89–90 Hyperphosphorylated tau protein 99 Lateral habenula 37
Gliomas 89 Hyperpolarization 15–16, 60 Lateral hypothalamus 61, 63
Glossopharyngeal nerve 23 Hypertension 57, 70 Lateral prefrontal cortex 37
Glucocerebrosidase (GBA) 101 Hypnagogic hallucination 63 Lens 18–19
Glucocorticoid hormones 69 Hypomanic 79 Lentivirus 117
Glutamate 16, 35, 61, 64, 77–78, 84, 87, Hypothalamus 11, 13, 36, 61, 63–64, Leptin 69
89, 100, 103 66–69, 79 Lewy body 98, 101
Golgi tendon organs 29 Limbic system 11, 25, 51–52, 79, 82, 120
Gonadotropin-releasing hormone (GnRH) Longitudinal studies 51
68–69 I Long-term depression (LTD) 35
Grand mal seizures 75 Immune system 5, 70, 90, 92–93, 100, Long-term memory 34–35, 41
Gray matter 25, 52–53, 73, 106 107, 115, 117 Long-term potentiation (LTP) 35
Gray matter density 52 Immunotherapy 90 Lou Gehrig’s disease (ALS) 96, 102, 113
Grid cells 34 Implicit memory 34 Luteinizing hormone (LH) 68–69
Grip force 31 Incus (anvil) 21
Growth cone 47 Induced pluripotent stem (iPS) cells 102
Gustatory cortex 23 Inflammatory responses 57 M
Inhibitory interneurons 14, 29 Machine-learning 116
Inhibitory neurons 14, 16, 31 Macula 19
H Inner ear 21–22 Macular degeneration 19, 21
Hair cells 21–22 Insomnia 61–62, 67, 70, 79, 85 Magnetic resonance imaging (MRI)
Hallucinations 80, 97, 109 Insula 23, 36, 116 51–52, 65, 90, 92–93, 102, 106,
Hearing 21–22, 46, 51–52, 63, 74 Insular cortex 36, 120 110–111, 114, 116
Heart attack 8, 62, 70 Interneurons 14, 19, 45 Magnetoencephalography (MEG) 111
Hemineglect syndrome 65 Involuntary (autonomic) nervous systems Major depression 78–79, 116
Heroin 82–83 69 Malignant 88

index continued
Malleus (hammer) 21 Movements 10–13, 20, 26–31, 32, 41, 68, 76–78, 82–83, 86–87, 98, 109,
Manic 79–80 43, 50, 60–61, 72, 102–103, 106, 121
Marijuana 85 110, 113 Neurotrophic factors 58, 103, 115
Mass spectrometry 110 MPTP 101–102 Neurotrophins 35
Medial prefrontal cortex 43 Multiple sclerosis (MS) 92 Nicotine 80, 83–84, 86, 102
Median eminence 68 Muscle fibers 27, 29 Nicotinic acetylcholine receptors 83
Medulla 11, 13, 69 Muscles 6, 13–14, 26–30, 45–46, 60, 62, NMDA receptor antagonist 100
Megalencephaly 45 69–70, 84, 91, 103, 113 N-methyl-D-aspartate (NMDA) receptor
Melanin-concentrating hormone 63 Muscle spindles 28–29 16, 35, 84, 100
Melatonin 67 Mutations 17, 41, 46, 72, 99, 101, 103, Nociceptors 24
Memantine 100 107–108, 117 Nodes of Ranvier 48
Membrane potential 15–16 Myelin 15, 25, 48, 50–53, 55, 92, 106 Nondeclarative memory 34, 55
Memory 6, 11, 13, 16, 32–36, 38–39, Myelination 50–52 Nonsteroidal anti-inflammatory drugs
41–43, 45, 51–52, 54–56, 58, 65, 70, Myelin sheath 25, 48, 92 (NSAIDs) 94
72, 74, 77–78, 80, 83–85, 89, 91–94, Norepinephrine 48, 61, 63, 78–79
97–101, 104, 113–114, 119–120 Nucleus accumbens 37, 43, 64
Meninges 89 N
Meningioma 89 Naloxone 83
Menstrual cycle 69 Narcolepsy 61, 63, 86 O
Mentalizing 43 Near-infrared spectroscopy (NIRS) 111 Obsessive-compulsive disorder (OCD)
Mesoderm 44–45 Negative feedback loops 68–69 76–77
Mesolimbic pathway 37 Neocortex 61, 99 Occipital lobes 11–12, 33
Metabolic stressors 70 Nerve growth factor 48, 115 Occipitotemporal cortex 40, 74
Metastatic brain tumors 88 Nerve ring 47 Olfactory bulbs 12, 23, 56
Methamphetamine 86–87 Netrin 47 Olfactory cortex 23
Methylphenidate 73, 86 Neural induction 44–45 Oligodendrocytes 15, 50, 116
Methylprednisolone 91 Neurite outgrowth inhibitor 115–116 Oligonucleotide 104
Microarrays 107 Neuritic plaques 99–100 Omega-3 fatty acids 57
Microcephaly 45 Neurodegenerative diseases 4, 48, 57, Opioid receptors 25, 82–83, 95
Microdialysis 109–110 96–104, 110, 115 Opioids 25, 81–83, 94
Microglia 15, 56–57, 87, 99, 115 Neuroeconomics 120 Optic chiasm 20–21
Microtubules 16, 99 Neuroendocrine hormones 69 Optic nerve 12, 19–20, 92–93
Midbrain 11–12, 30, 36–37, 46, 101 Neuroendocrine system 68 Optogenetics 63, 107
Migration 44–46, 50, 74 Neurofibrillary tangles 98 Orexin 61, 63
Mild cognitive impairment 56 Neurogenesis 22–23, 45, 56, 58 Orexin neurons 61, 63, 67
Mitochondria 56, 74, 99, 101, 104 Neuroimaging 72, 78, 98, 113, 116 Oval window 21–22
Mitochondrial DNA 56 Neurolaw 119 Oxidative damage 56
Mood 26, 37, 59, 65, 71, 78–79, 82, 84, Neuroleptic 77 Oxidative stress 56, 99
93–94, 103, 114 Neuromodulators 17 Oxytocin 68, 73, 78, 87, 120
Mood disorders 77–78, 114 Neuropathic pain 25
Morphine 25, 37, 82, 94–95 Neuropeptides 61
Motivations 63 Neuroplasticity 58 P
Motor cortex 30, 43, 60, 111 Neuroprostheses 113 Pain 8, 17, 24–25, 36–37, 79, 81, 83–85,
Motor neurons 27–29, 30, 45, 48, 103 Neurotoxicity 99 88–89, 91–95, 110, 114, 121
Motor unit 27 Neurotransmitters 15–17, 35, 61, 63–64, Panic disorder 77

Parahippocampal region 32–34 Processing speed 55 Rods 19
Paralysis 30, 63, 91, 95, 103, 112 Progenitor cells 45 Rohypnol 87
Paranoia 97 Progesterone 64, 69
Parasympathetic branch 69 Projection fibers 55
Paraventricular nucleus 67–68 Proliferation 44–47, 50, 72, 89 S
Parietal lobes 11–12, 20, 33, 39, 40, Prosopagnosia (face blindness) 39, 65 Saltatory conduction 48
42–43 Prostaglandins 17, 25, 94 Schizophrenia 8, 49, 65, 76–80, 83, 85,
Parkin 101 Pruning 48, 51 107, 109, 114, 116–117
Parkinson’s disease 4, 8, 30, 57, 62, PSEN1 99 Sclerosis 92
77, 80, 96, 98, 100–102, 110, 113, PSEN2 99 Secondary generalized seizures 75
115–117 Psychosis 79, 121 Secondary-progressive MS 93
Partial seizures 75 Psychostimulants 86 Second messengers 35
Passive immunization 100 Pupil 18 Selective attention 55, 65
Periaqueductal gray 25, 36–37 Selective serotonin reuptake inhibitors
Peripheral neuropathy 92 (SSRIs) 8, 77–79
Petit mal seizures 75 Q Semantic memory 33, 39, 55
Pharmacology 110 Quadriplegic 113 Semaphorin 47
Photoreceptors 12, 19–21, 67 Sensory receptors 13, 28, 31
Pineal gland 67 Serotonin 56, 61, 63–64, 77, 86–87
Pituitary gland 11, 68–69, 79, 82 R Shaking 100
Place cells 34 Radioactive chemical marker 98 Short-term memory 34, 38, 41, 84–85,
Plaques 98–100, 102, 106–107, 111, 115 Rapid eye movement (REM) sleep 60–63 99
Plasticity 6, 52 Receptive field 19–20 Skeletal muscles 26–27
Polygraph tests 119 Receptors 6, 13, 16–17, 19, 28–29, 31, Sleep 11, 13, 37, 59–63, 67, 70, 78,
Pons 11 35, 37, 47, 56, 62, 67–69, 94–95, 84–86, 91, 97–98, 100, 106–107, 116
Positron emission tomography (PET) 65, 99–100 Sleep apnea 62
111 Reciprocal inhibition 29 Slow wave sleep (SWS) 60, 60–62
Posterior cingulate cortex 65 Recreational drugs 85–87 Smell (olfaction) 22–24
Postsynaptic neuron 16, 35, 47 Reflexes 6, 11, 28–30 SOD1 103
Post-traumatic epilepsy 91 Regeneration 49, 90, 115–116 Soma 15, 46
Post-traumatic stress disorder (PTSD) 35, Relapsing-remitting MS 93 Somatic (voluntary) nervous system 69
76–79, 85, 111 REM sleep behavior disorder 62 Somatosensory cortex 24
Precuneus 65 REM sleep generator 61 Sonic hedgehog 45
Predictive neuroimaging 116 Repeat kinase 2 (LRRK-2) 101 Spatial memory 34
Prefrontal cortex (PFC) 34, 36–37, 39, Reproduction 63, 68 Spatial neglect 65
41, 43, 53, 55, 65, 78–80, 86, 114, Resilience factors 76 Speech 11, 21–22, 31, 39–41, 84, 91, 93,
119 Resting tremor 100 95, 103
Premotor cortex 112 Reticular activating system 63 Spinal circuits 30
Presynaptic neuron 35, 47 Retina 12, 18–20, 61, 67 Spinal cord 11, 13, 24–29, 26–30, 36,
Primary auditory cortex 22 Rett syndrome 115 45–47, 55, 61, 67, 90–92, 95, 103,
Primary brain tumor 88–89 Reuptake 16 116
Primary motor cortex 112 Reward system 4, 37, 51, 77, 82, 85–86 Split-brain surgery 75
Primary-progressive MS 93 Right parietal cortex 65 Sporadic ALS 103
Primary visual cortex 12, 20–21 Riluzole 103 Squirrel monkeys 51
Prions 96 Rivastigmine 100 Stapes (stirrup) 21
Procedural memory 34, 55 RNA-guided enzymes 117

index continued
Stem cells 24, 74, 90–91, 95, 101–103, Tobacco 81–84, 86, 88 Voluntary (endogenous) attention 64
116–117 Tolerance 37, 81, 83, 86 Voluntary (somatic) nervous systems 69
Stereocilia 22 TOMM40 99
Stereotactic radiosurgery 89 Tonic-clonic seizures 75
Steroid 17, 89, 91, 93 Touch 13, 21, 24–25 W
Strabismus 21 Touch receptors 24 Wernicke’s aphasia 40
Strength 13, 25, 30, 35, 48, 82, 91, 103, Tourette’s syndrome 114 Wernicke’s area 22
106, 108, 114 Tracers 98, 106 White matter 50–53, 55, 75, 92, 106
Stress 37, 56, 59, 67–70, 76–79, 82, 85 Transcranial alternating current stimula- Withdrawal 81, 83–86
Stress response 37, 69, 70 tion (tACS) 114 Womb 50–51, 121
Stretch (myotatic) reflex 28 Transcranial direct current stimulation Word-form area 74
Striatum 37, 41, 102 (tDCS) 114 Working memory 34, 42–43, 52, 55–56,
Stroke 22, 39, 62, 65, 70, 83, 94–95, Transcranial magnetic stimulation (TMS) 114
112, 114, 116, 117 111, 114
Substantia nigra 30, 101 Transcription factors 70
Superoxide dismutase 103 Transduction 17–19
Superoxide radicals 103 Traumatic brain injuries (TBI) 90
Suprachiasmatic nucleus (SCN) 61, 67 TREM2 99
Supraoptic nuclei 68 Tremor 31, 80–81, 84, 93, 102, 113
Sympathetic branch 69 Trinucleotide 104
Synapse 5, 14–16, 34–35, 37, 47–48, Trophic factors 48, 115
50–51, 53, 55, 57–58, 79, 82, 87, Two-photon microscopy 52, 106
98–99, 106, 108–109 Two-point discrimination 24
Synaptic density 51 Tympanic membrane (eardrum) 21
Synaptic plasticity 35, 56, 106
Synaptic pruning 6, 51, 55
Synaptic vesicles 15 U
Synaptogenesis 50 UBQLN2 103
Undifferentiated cells 116
Unilateral neglect 65
T Upper brainstem 61
Tangles 98–99, 101
Targeted treatments 89–90
Taste buds 23 V
Taste (gustation) 22 Vagus nerves 23
Tau 98–99, 104 Vascular endothelial growth factor
Tectorial membrane 22 (VEGF) 103
Temporal lobes 7, 11–12, 20, 22–23, Vectors 117
32–33, 39–41, 52, 55 Ventral stream 20
Testosterone 64, 69, 120 Ventral tegmental area (VTA) 37
Tetrahydrocannabinol (THC) 85 Ventricular zone 46
Thalamus 11–13, 20, 22–25, 30, 36, 61, Ventrolateral preoptic (VLPO) nucleus 61
63, 102 Ventromedial prefrontal cortex 65
Thin spines 55 Vision 12, 18–21, 41, 46, 63, 89, 93
Tissue plasminogen activator (tPA) 95 Visual fields 21

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2 Brain Facts | society for neuroscience

CHAPTER 1 Brain Basics 10

CHAPTER 2 Senses & Perception 18

CHAPTER 4 Learning, Memory & Emotions 32

CHAPTER 5 Thinking, Planning & Language 38

CHAPTER 6 The Developing Brain 44

CHAPTER 7 Infant, Child & Adolescent Brain 49

CHAPTER 8 Adult & Aging Brain 53

CHAPTER 9 Brain States 59

CHAPTER 10 The Body in Balance 66

CHAPTER 11 Childhood Disorders 71

CHAPTER 12 Psychiatric Disorders 76

CHAPTER 14 Injury & Illness 88

CHAPTER 15 Neurodegenerative Diseases 96

CHAPTER 16 Kinds of Research 105

CHAPTER 17 Solving Human Problems 112

CHAPTER 18 Neuroscience in Society 118

society for neuroscience | Brain Facts 3

4 Brain Facts | society for neuroscience

Your Complex Brain

How Neurons Communicate

society for neuroscience | Brain Facts 5

How Your Brain Processes Information

How Experience Shapes Your Brain

6 Brain Facts | society for neuroscience

The Power of Language

society for neuroscience | Brain Facts 7

The Source of Curiosity

How Research Benefits Human Health

8 Brain Facts | society for neuroscience

society for neuroscience | Brain Facts 9

Major Brain Landmarks

The frontal lobes are at the front of

integrating them into complex

society for neuroscience | Brain Facts 11

12 Brain Facts | society for neuroscience

Neurons are organized into a

society for neuroscience | Brain Facts 13

sends a single electrical signal to mul-

14 Brain Facts | society for neuroscience

Ion Channels and

neuron’s likelihood of generating an

society for neuroscience | Brain Facts 15

Many different molecules act

16 Brain Facts | society for neuroscience

society for neuroscience | Brain Facts 17

Perception tastes, and smells. Instead, you are sur-

the axons of ganglion cells exit the

society for neuroscience | Brain Facts 19

20 Brain Facts | society for neuroscience

society for neuroscience | Brain Facts 21

Making Sense of Sound